Enhancing diagnosis of disorder through artificial intelligence and mobile health technologies without compromising accuracy

ABSTRACT

A computer system for generating a diagnostic tool by applying artificial intelligence to an instrument for diagnosis of a disorder, such as autism. For autism, the instrument can be a caregiver-directed set of questions designed for an autism classification tool or an observation of the subject in a video, video conference, or in person and associated set of questions about behavior that are designed for use in a separate autism classification tool. The computer system can have one or more processors and memory to store one or more computer programs having instructions for generating a highly statistically accurate set of diagnostic items selected from the instrument, which are tested against a first test using a technique using artificial intelligence and a second test against an independent source. Also, a computer implemented method and a non-transitory computer-readable storage medium are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S. patentapplication Ser. No. 15/227,656 filed Aug. 3, 2016, which is acontinuation application of application Ser. No. 14/354,032 filed Apr.24, 2014, which is a 35 U.S.C. § 371 National Phase Entry Application ofInternational Application No. PCT/US2012/061422 filed Oct. 23, 2012,which designates the U.S., and which claims the benefit of, and priorityto, U.S. Provisional Patent Application No. 61/550,695, filed on Oct.24, 2011, entitled “SHORTENING THE BEHAVIORAL DIAGNOSIS OF AUTISMTHROUGH ARTIFICIAL INTELLIGENCE AND MOBILE HEALTH TECHNOLOGIES,” theentire disclosure of each application is hereby incorporated herein byreference. Also, this application claims the benefit of, and priorityto, U.S. Provisional Patent Application No. 61/567,572, filed on Dec. 6,2011, entitled “Diagnosis of Autism with Reduced Testing,” the entiredisclosure of which is hereby incorporated herein by reference. Thisapplication claims priority to U.S. Provisional Patent Application No.61/682,110, filed on Aug. 10, 2012, entitled “ENHANCING DIAGNOSIS OFDISORDER THROUGH ARTIFICIAL INTELLIGENCE AND MOBILE HEALTH TECHNOLOGIESWITHOUT COMPROMISING ACCURACY,” the entire disclosure of which is herebyincorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to a method, system,non-transitory computer-readable medium and apparatus for diagnosis ofan illness or disorder. Specifically, in one embodiment, a mobile (e.g.,web, smart device or the like) tool that enables rapid video-basedscreening of children for risk of having an autism spectrum disorder isdisclosed. The tool is designed to speed the process of diagnosis andincrease coverage of the population.

SUMMARY OF THE INVENTION

When a caregiver, such as a parent, suspects that a care recipient, suchas a child or elderly person, might have an undiagnosed, misdiagnosed,untreated or undertreated disorder, such as an autism spectrum disorderor dementia, it is important that the caregiver obtain a fast, accuratediagnosis. Problems exist in that known methods of assessment anddiagnosis of a mental disorder are difficult to obtain due to a lack ofaccess to a sufficient facility, the cost of a diagnosis, the timeinvolved in obtaining a diagnosis and differences in a subject'sbehavior outside of routine conditions, such as differences in behaviorexhibited at home versus in a clinical environment.

Autism rates continue to rise with more and more children being referredfor autism screening every day. Behavioral exams currently used fordiagnosis tend to be long and the diagnosis process as a whole iscumbersome for families. In addition, clinical professionals capable ofadministering the exams tend to be too few and well above capacity. Theaverage time between initial evaluation and diagnosis for a child livingin a large metropolitan area is over one year and approaches 5 years forfamilies living in more remote areas. The delay in diagnosis is not onlyfrustrating for families, but prevents many children from receivingmedical attention until they are beyond developmental time periods whentargeted behavioral therapy would have had maximal impact. The inventioncan include a mobile-health technology to reshape the landscape ofautism screening and diagnosis in order to provide increasingly earlierrecognition of autism for all families, including those in remote areas,thereby enabling rapid delivery of treatment and therapy early, often,and in the time window when it has greatest impact.

Autism spectrum disorders have a relatively high incidence rate in thegeneral population, i.e., 1 in 150 children are affected. Autism isdefined by impairments in three core domains: social interaction,language, and restricted range of interests. Autism has a geneticcomponent and is largely diagnosed through observation and analysisbehavior. Specifically, there is a defined, strong genetic basis forautism, for example, concordance rates for monozygotic twins are near90%. Further, a significant male bias has been observed, i.e., 4 malesto 1 female.

One known tool for autism diagnosis is the Autism Diagnostic InterviewRevised (ADI-R) (Lord, et al., “Autism Diagnostic Interview-Revised: arevised version of a diagnostic interview for caregivers of individualswith possible pervasive developmental disorders,” J Autism Dev Disord,1994, 24(5):659-685). ADI-R utilizes a semi-structured,investigator-based interview for caregivers; was originally developed asa research instrument, but clinically useful; is keyed to DSM-IV/ICD-10Criteria; has high inter-rater reliability; utilizes 93 main questionsand numerous sub-elements that sum to over 150 items; and takes about2.5-3 hours to administer.

Another known tool for autism diagnosis is the Autism DiagnosticObservation Schedule (ADOS) (Lord, et al., “The autism diagnosticobservation schedule-generic: a standard measure of social andcommunication deficits associated with the spectrum of autism,” Journalof Autism and Developmental Disorders, 2000, 30(3): 205-223). ADOS is anunstructured play assessment, which elicits the child's own initiations.The assessment can include social initiations, play, gestures, requests,eye contact, joint attention, etc. pressed for, observed, and coded byexaminer. Using ADOS, an examiner pulls for target behaviors throughspecific use of toys, activities, and interview questions; andstereotypical behaviors, sensory sensitivities, aberrant behaviors andthe like are also observed and coded. ADOS typically requires about30-60 minutes of observation, followed by about 15 minutes of scoring;utilizes 29 questions, of which 12-14 are used for scoring; and requiresabout 60-90 minutes for total assessment. For example, the AutismDiagnostic Observational Schedule-Generic (ADOS-G) exam is divided intofour modules. Each of the modules is geared towards a specific group ofindividuals based on their level of language and to ensure coverage forwide variety of behavioral manifestations. Module 1, containing 10activities and 29 items, is focused on individuals with little or nolanguage and therefore most typical for assessment of younger children.

One problem with known tools for autism diagnosis is that diagnosis isoften significantly delayed. The average age of initial diagnosis is 5.7years; 27% remain undiagnosed at age 8; the average age from initialindication to clinical diagnosis is 13 months; and diagnosiscapabilities in rural areas is extremely limited. (Shattuck, et al.,“Timing of identification among children with an autism spectrumdisorder: findings from a population-based surveillance study,” Journalof the American Academy of Child and Adolescent Psychiatry, 2009,48(5):474-483. Wiggins, et al., “Examination of the time between firstevaluation and first autism spectrum diagnosis in a population-basedsample,” Journal of developmental and behavioral pediatrics, IDBP 2006,27(2 Suppl):579-87.)

Another problem with known tools for autism diagnosis is that the knowntools often require that the subject and caregiver travel long distancesto a clinical facility for diagnosis. As a result, the generalpopulation has limited access to appropriate resources for autismdiagnosis. For example, in Massachusetts, having a population of about6.6 million people (U.S. Census Bureau, July 2011), there are less than10 clinical facilities for diagnosis of autism, or just one clinicalfacility for diagnosis of autism for every 660,000 people.

Thus, there is a need for improvements to existing autism diagnosissystems, tools and methods, including alternatives to the existingsystems, tools and methods.

According to the present invention, accurate identification oflikelihood of a disorder in a subject, which normally involves atime-consuming and resource-intensive process, can be achieved in amatter of minutes.

In one embodiment of the present invention, a test is provided thattakes about 7 questions to complete and requires creation and submissionof a relatively short home video to a system according to the presentinvention.

According to the present invention, caregivers are empowered to detect adisorder as early as possible and plan an intervention with therapy asearly as possible, which is highly desirable in the treatment ofdisorders such as autism.

One advantage of the present invention is, for example, facilitating theprovision of therapy for a subject as early as possible.

For example, with autism, the average diagnosis age is around 5 yearsold. An autism diagnosis of a subject at age 5 means that the subjecthas already passed through critical developmental windows where earlybehavioral therapy would have had a positive impact.

The present invention may be conducted on-line with no waiting time.

The present invention improves access to a powerful screening tool for adisorder such as autism.

The present invention can be used by nearly anyone, particularly aperson having a camera and an internet connection.

The present invention may be used in conjunction with a remotely locatedteam of trained researchers, trained to score a video uploaded by aperson utilizing the present invention.

The present invention has a distinct advantage over known methods ofdiagnosing autism in children in that children are normally more relaxedat home than in a doctor's office or clinical environment. With thepresent invention, a child may be observed while operating within andbehaving within his or her home environment, with their siblings and soon. Using the present invention, trained reviewers are able to see signsof a disorder, such as autism, more easily and more rapidly than withknown tools.

The present invention is highly accurate.

Known diagnosis methods for disorders can take several hours tocomplete. Also, with known methods, a family may have to go to adoctor's office, fill out lengthy forms, and be evaluated throughout theday.

It has been discovered, unexpectedly, that for either of the knownautism exams, not all of the measurements (e.g., input to an algorithm,which can be descriptions of observed behavior in the format that thealgorithm requires, the answers to questions about observed behaviors inthe format that the algorithm requires, observations or questions) arerequired to produce an accurate diagnosis. Through experimentationaccording to the invention, autism can be diagnosed at perfect accuracywith as few as 8 of the 29 ADOS-G module 1 items, or as few as 7 out ofthe 93 ADI-R questions. The required number of measurements can be evenlower without significant loss of diagnostic accuracy, both in terms ofspecificity and sensitivity.

Due to the greatly reduced number of measurements required to make thediagnosis, the diagnosis resulting from the invention can be made withnear perfect accuracy on video clips, instead of live or interactiveinterview with the subject and care provider. In some embodiments,therefore, the video clip includes observation of a subject in anon-clinical environment, such as home. In some embodiments, the patientbeing video recorded is asked a number of questions that are determinedto be suitable for diagnosing autism in the patient by the presentdisclosure. In one aspect, the video clip is shorter than about 10minutes. In another aspect, the video clip is between about 2 and 5minutes long. In certain embodiments, the video clips is recorded and/ordisplayed on a mobile device, or displayed on a web interface.

As the shortened behavioral instruments can be used both individuallyand combined with each other or each or both combined for the assessmentof short, <10 minute video clips of the subject, either in or out ofclinical environments, the entire collection of discoveries according tothe invention can be integrated for the creation of a mobile healthsystem for rapid, highly accurate, and comprehensive assessment of asubject using a mobile device or web interface.

The present invention can involve the use of a behavioral instrument forrapid screening of autism using home videos taken on hand-held recordersand smart phones. The behavioral instrument can be administered via theweb in less than 5 minutes with accuracy identical to that of thegold-standard instruments used for autism diagnosis today. The analysisresults in risk assessment reports that give families an unintimidatingand empowering means to understand their child's behavior while alsospeeding the connection between families and the clinical carefacilities that can offer further evaluation and care.

The present invention can include the following: (1) Novel algorithmsfor screening and risk assessment using 2-5 minute video clips of thesubject. (2) Web portal for secure access to risk assessment report. (3)A carefully designed risk report for clinicians that includes apreliminary diagnosis, the video of the subject, recommendations fortherapy (e.g., ABA, speech therapy) and detailed summary of scoring.This report is made available via secure access to a clinical carefacility prior to clinical workup of the subject. (4) A carefullydesigned risk report for the care provider that includes arecommendation for follow up, contact details and locations of nearestclinical facilities offering diagnosis and treatment, and a collectionof educational materials to browse for more information about thesubject's potential condition. (5) A growing video repository andassociated behavioral score sheets for use in improving recognition ofautism and increasing standardization of autism diagnosis.

The present invention can utilize data mining to improve the diagnosisprocess. For example, the present invention can utilize data from largerepositories such as the Autism Genetic Resource Exchange, the SimonsSimplex Collection and the Autism Consortium. The present invention canutilize Retrospective analysis of shore sheets such as ADI-R and ADOS,which have large numbers of participants. The present invention usesobjective methods to avoid bias. The present invention can utilizeartificial intelligence and machine learning. The present inventionutilizes classification of diagnostic questions, tested accuracy of thediagnostic questions and alters the known diagnostic instruments in amanner that maximizes efficiency of the diagnosis with little or nonegative affect on the accuracy of the diagnosis.

One aspect of the present invention includes an algorithm forparent/caregiver-directed assessment strategy for diagnosis of autismspectrum disorder.

Another aspect of the present invention includes an algorithm forobservation of a subject (individual at or above approximately 13 monthsof age) and assessment strategy for diagnosis of autism spectrumdisorder.

Yet another aspect of the present invention includes a machine learningprotocol for analysis of behavioral data that results in improved formsof testing of autism spectrum disorder, and other behaviorally diagnoseddisorders including but not limited to ADHD, PTSD, and mild cognitiveimpairment.

Still another aspect of the present invention includes infrastructure,including a database management system, software, and computingequipment associated with the delivery of algorithms disclosed herein.

Another aspect of the present invention includes a quantitative scorefor diagnosis of subjects and for placement of subjects on a continuousscale from least extreme or severe, to most extreme or severe. Forexample, in the case of autism spectrum disorders this scale would rangefrom the most severe form of autism to the most extreme phenotype in aneurotypical population.

Yet another aspect of the present invention includes a repository ofquantitative scores valuable for the diagnosis of subjects with autismspectrum disorder, for assessment of confidence in diagnosis of subjectswith autism spectrum disorder, and for the stratification of subjectsfor subsequent analysis including further phenotypicevaluation/categorization as well as genotypicevaluation/categorization.

Still another aspect of the present invention includes user interfacetechnology developed for use on personal computers and smart devicessuch as iPhones, iPads, iPods, and tablets.

Another aspect of the present invention includes training materialsneeded for administration of algorithms described above.

Yet another aspect of the present invention includes training materialsneeded for training professionals in video analysis and scoring forobservation-based diagnosis of autism spectrum disorder.

Still another aspect of the present invention includes a proprietary setof criteria for videos to be used in the video-based analysis autismspectrum disorders.

Another aspect of the present invention includes a system for clinicalimpact report generation that is delivered to health care professionalsfor further analysis of subjects at risk of autism spectrum disorders.

Yet another aspect of the present invention includes the structure andcontent of a clinical impact report intended for use by health careprofessionals for rapid assessment of subjects at risk of autismspectrum disorder.

Still another aspect of the present invention includes a system forembedding the contents from the training materials needed for trainingprofessionals in video analysis and scoring for observation-baseddiagnosis of autism spectrum disorder in a web-framework for restrictedaccess by health care professionals with appropriate access credentials.

Another aspect of the present invention includes a system for generationof a report that is directed to parents and caregivers of subjectstested by algorithms mentioned above.

Yet another aspect of the present invention includes the structure andcontent of a parent/caregiver report intended for rapid knowledgetransfer and for rapid connection between parent/caregiver and clinicalservices.

Still another aspect of the present invention includes code, softwareand infrastructure for secure, scalable storage of videos of subjectswith neurodevelopmental delays including autism spectrum disorders.

Yet another aspect of the present invention includes code, software, andinfrastructure for the secure, scalable management of videos of subjectswith neurodevelopmental delays including autism spectrum disorders.

In one aspect, provided herein is a computer implemented method ofgenerating a diagnostic tool by applying artificial intelligence to aninstrument for diagnosis of a disorder, wherein the instrument comprisesa full set of diagnostic items, the computer implemented methodcomprising: on a computer system having one or more processors and amemory storing one or more computer programs for execution by the one ormore processors, the one or more computer programs includinginstructions for: testing diagnostic items from the instrument using atechnique using artificial intelligence; determining from the testingthe most statistically accurate set of diagnostic items from theinstrument; selecting a set of the most statistically accuratediagnostic items from the instrument; determining the accuracy of theset of the most statistically accurate diagnostic items from theinstrument by testing the set of the most statistically accuratediagnostic items from the instrument against an independent source; andgenerating the diagnostic tool for diagnosis of the disorder.

In one embodiment of this aspect, the instrument is the AutismDiagnostic Interview-Revised and the disorder is autism, the full set ofdiagnostic items consists of 153 diagnostic items, and the diagnostictool consists of 7 diagnostic items.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2.5 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 7 diagnostic itemsare comprehension of simple language, reciprocal conversation,imaginative play, imaginative play with peers, direct gaze, group playwith peers and age when abnormality first evident.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, ConjunctiveRule,DecisionStump, Filtered Classifier, J48, J48graft, JRip, LADTree, NNge,OneR, OrdinalClassClassifier, PART, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisescompleted Autism Diagnostic Interview-Revised score sheets from SimonsFoundation, Boston Autism Consortium, National Database for AutismResearch or The Autism Genetic Research Exchange.

In another embodiment of this aspect, the following types of diagnosticitems are removed from the 153 diagnostic items: diagnostic itemscontaining a majority of exception codes indicating that the diagnosticitem could not be answered in a desired format, diagnostic itemsinvolving special isolated skills and diagnostic items with hand-writtenanswers.

In another embodiment of this aspect, the instrument is the AutismDiagnostic Observation Schedule-Generic and the disorder is autism, thefull set of diagnostic items consists of four modules, the first of thefour modules consists of 29 diagnostic items, and the diagnostic toolconsists of 8 diagnostic items from the first module.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2-4 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 8 diagnostic itemsare frequency of vocalization directed to others, unusual eye contact,responsive social smile, shared enjoyment in interaction, showing,spontaneous initiation of joint attention, functional play with objectsand imagination/creativity.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, DecisionStump, FT,J48, J48graft, Jrip, LADTree, LMT, Nnge, OneR, PART, RandomTree,REPTree, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisesscore sheets for the first of the four modules from Boston AutismConsortium or Simons Simplex Collection.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: training an analyst to review a videoof a test subject; and scoring the video using the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: generating a report based on thediagnostic tool, the report comprises a suggested clinical action.

In another embodiment of this aspect, the report further comprises atleast one of the following: a link to a video of a test subject; atleast one chart depicting results of the diagnostic tool; a list offacilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action; and a map depicting locationsof facilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: testing a test subject with thediagnostic tool; and testing the test subject with the full set ofdiagnostic items if the test subject demonstrates a need for the fullset of diagnostic items based on the results of the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: treating a test subject for thedisorder.

In another aspect, provided herein is a computer system for generating adiagnostic tool by applying artificial intelligence to an instrument fordiagnosis of a disorder, the instrument comprises a full set ofdiagnostic items, the computer system comprising: one or moreprocessors; and memory to store: one or more computer programs, the oneor more computer programs comprising instructions for: generating ahighly statistically accurate set of diagnostic items selected from theinstrument, the highly statistically accurate set of diagnostic itemsfrom the instrument pass a first test using a technique using artificialintelligence and a second test against an independent source.

In another embodiment of this aspect, the instrument is the AutismDiagnostic Interview-Revised and the disorder is autism, a full set ofdiagnostic items from the Autism Diagnostic Interview-Revised consistsof 153 diagnostic items, and the diagnostic tool consists of 7diagnostic items.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2.5 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 7 diagnostic itemsare comprehension of simple language, reciprocal conversation,imaginative play, imaginative play with peers, direct gaze, group playwith peers and age when abnormality first evident.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, ConjunctiveRule,DecisionStump, Filtered Classifier, J48, J48graft, JRip, LADTree, NNge,OneR, OrdinalClassClassifier, PART, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisescompleted Autism Diagnostic Interview-Revised score sheets from SimonsFoundation, Boston Autism Consortium, National Database for AutismResearch or The Autism Genetic Research Exchange.

In another embodiment of this aspect, the following types of diagnosticitems are removed from the 153 diagnostic items: diagnostic itemscontaining a majority of exception codes indicating that the diagnosticitem could not be answered in a desired format, diagnostic itemsinvolving special isolated skills and diagnostic items with hand-writtenanswers.

In another embodiment of this aspect, the instrument is the AutismDiagnostic Observation Schedule-Generic and the disorder is autism, afull set of diagnostic items consists of four modules, the first of thefour modules consists of 29 diagnostic items, and the diagnostic toolconsists of 8 diagnostic items from the first module.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2-4 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 8 diagnostic itemsare frequency of vocalization directed to others, unusual eye contact,responsive social smile, shared enjoyment in interaction, showing,spontaneous initiation of joint attention, functional play with objectsand imagination/creativity.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, DecisionStump, FT,J48, J48graft, LADTree, LMT, Nnge, OneR, PART, RandomTree, REPTree,Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisesscore sheets for the first of the four modules from Boston AutismConsortium or Simons Simplex Collection.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: training an analyst to review a videoof a test subject; and scoring the video using the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: generating a report based on thediagnostic tool, the report comprises a suggested clinical action.

In another embodiment of this aspect, the report further comprises atleast one of the following: a link to a video of a test subject; atleast one chart depicting results of the diagnostic tool; a list offacilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action; and a map depicting locationsof facilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action.

In another aspect, provided herein is a non-transitory computer-readablestorage medium storing one or more computer programs configured to beexecuted by one or more processing units at a computer comprisinginstructions for: testing diagnostic items from the instrument using atechnique using artificial intelligence; determining from the testingthe most statistically accurate set of diagnostic items from theinstrument; selecting a set of the most statistically accuratediagnostic items from the instrument; determining the accuracy of theset of the most statistically accurate diagnostic items from theinstrument by testing the set of the most statistically accuratediagnostic items from the instrument against an independent source; andgenerating the diagnostic tool for diagnosis of the disorder.

In one embodiment of this aspect, the instrument is the AutismDiagnostic Interview-Revised and the disorder is autism, the full set ofdiagnostic items consists of 153 diagnostic items, and the diagnostictool consists of 7 diagnostic items.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2.5 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 7 diagnostic itemsare comprehension of simple language, reciprocal conversation,imaginative play, imaginative play with peers, direct gaze, group playwith peers and age when abnormality first evident.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, ConjunctiveRule,DecisionStump, Filtered Classifier, J48, J48graft, JRip, LADTree, NNge,OneR, OrdinalClassClassifier, PART, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisescompleted Autism Diagnostic Interview-Revised score sheets from SimonsFoundation, Boston Autism Consortium, National Database for AutismResearch or The Autism Genetic Research Exchange.

In another embodiment of this aspect, the following types of diagnosticitems are removed from the 153 diagnostic items: diagnostic itemscontaining a majority of exception codes indicating that the diagnosticitem could not be answered in a desired format, diagnostic itemsinvolving special isolated skills and diagnostic items with hand-writtenanswers.

In another embodiment of this aspect, the instrument is the AutismDiagnostic Observation Schedule-Generic and the disorder is autism, thefull set of diagnostic items consists of four modules, the first of thefour modules consists of 29 diagnostic items, and the diagnostic toolconsists of 8 diagnostic items from the first module.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2-4 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 8 diagnostic itemsare frequency of vocalization directed to others, unusual eye contact,responsive social smile, shared enjoyment in interaction, showing,spontaneous initiation of joint attention, functional play with objectsand imagination/creativity.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, DecisionStump, FT,J48, J48graft, Jrip, LADTree, LMT, Nnge, OneR, PART, RandomTree,REPTree, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisesscore sheets for the first of the four modules from Boston AutismConsortium or Simons Simplex Collection.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: training an analyst to review a videoof a test subject; and scoring the video using the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: generating a report based on thediagnostic tool, the report comprises a suggested clinical action.

In another embodiment of this aspect, the report further comprises atleast one of the following: a link to a video of a test subject; atleast one chart depicting results of the diagnostic tool; a list offacilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action; and a map depicting locationsof facilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: testing a test subject with thediagnostic tool; and testing the test subject with the full set ofdiagnostic items if the test subject demonstrates a need for the fullset of diagnostic items based on the results of the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: treating a test subject for thedisorder.

In another aspect, provided herein is a non-transitory computer-readablestorage medium storing one or more computer programs configured to beexecuted by one or more processing units at a computer comprisinginstructions for: generating a highly statistically accurate set ofdiagnostic items selected from the instrument, the highly statisticallyaccurate set of diagnostic items from the instrument pass a first testusing a technique using artificial intelligence and a second testagainst an independent source.

In one embodiment of this aspect, the instrument is the AutismDiagnostic Interview-Revised and the disorder is autism, a full set ofdiagnostic items from the Autism Diagnostic Interview-Revised consistsof 153 diagnostic items, and the diagnostic tool consists of 7diagnostic items.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2.5 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 7 diagnostic itemsare comprehension of simple language, reciprocal conversation,imaginative play, imaginative play with peers, direct gaze, group playwith peers and age when abnormality first evident.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, ConjunctiveRule,DecisionStump, Filtered Classifier, J48, J48graft, JRip, LADTree, NNge,OneR, OrdinalClassClassifier, PART, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisescompleted Autism Diagnostic Interview-Revised score sheets from SimonsFoundation, Boston Autism Consortium, National Database for AutismResearch or The Autism Genetic Research Exchange.

In another embodiment of this aspect, the following types of diagnosticitems are removed from the 153 diagnostic items: diagnostic itemscontaining a majority of exception codes indicating that the diagnosticitem could not be answered in a desired format, diagnostic itemsinvolving special isolated skills and diagnostic items with hand-writtenanswers.

In another embodiment of this aspect, the instrument is the AutismDiagnostic Observation Schedule-Generic and the disorder is autism, afull set of diagnostic items consists of four modules, the first of thefour modules consists of 29 diagnostic items, and the diagnostic toolconsists of 8 diagnostic items from the first module.

In another embodiment of this aspect, a time for administering the fullset of diagnostic items is about 2-4 hours, and a time for administeringthe diagnostic tool is less than about an hour.

In another embodiment of this aspect, subjects of the 8 diagnostic itemsare frequency of vocalization directed to others, unusual eye contact,responsive social smile, shared enjoyment in interaction, showing,spontaneous initiation of joint attention, functional play with objectsand imagination/creativity.

In another embodiment of this aspect, the technique using artificialintelligence is a machine learning technique.

In another embodiment of this aspect, the machine learning technique isone from the group consisting of: ADTree, BFTree, DecisionStump, FT,J48, J48graft, Jrip, LADTree, LMT, Nnge, OneR, PART, RandomTree,REPTree, Ridor and SimpleCart.

In another embodiment of this aspect, the machine learning technique isADTree.

In another embodiment of this aspect, the independent source comprisesscore sheets for the first of the four modules from Boston AutismConsortium or Simons Simplex Collection.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: training an analyst to review a videoof a test subject; and scoring the video using the diagnostic tool.

In another embodiment of this aspect, the one or more computer programsfurther comprise instructions for: generating a report based on thediagnostic tool, the report comprises a suggested clinical action.

In another embodiment of this aspect, the report further comprises atleast one of the following: a link to a video of a test subject; atleast one chart depicting results of the diagnostic tool; a list offacilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action; and a map depicting locationsof facilities or clinicians, the facilities or clinicians are capable ofperforming the suggested clinical action.

In another aspect, provided herein is a method for diagnosing adisorder, comprising determining whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality: (a) comprises a set of specificbehaviors and measurements thereof identified after machine learninganalysis on the Autism Diagnostic Observation Schedule-Generic (ADOS-G)first module, (b) does not include measurement items based on the“response to name” activity of the ADOS-G first module, or (c) does notinclude measurement items based on the “response to joint attention”activity of the ADOS-G first module, and the determination is performedby a computer suitably programmed therefor.

In one embodiment of this aspect, the method further comprises takingthe plurality of measurements from the subject.

In another embodiment of this aspect, the plurality consists of 8measurement items selected from the ADOS-G first module.

In another embodiment of this aspect, the plurality does not includemeasurement items based on the “response to name” activity or the“response to joint attention” activity of the ADOS-G first module.

In another embodiment of this aspect, the plurality consists essentiallyof measurements items selected from the ADOS-G first module.

In another embodiment of this aspect, the multivariate mathematicalalgorithm comprises alternating decision tree (ADTree).

In another embodiment of this aspect, the determination achieves agreater than about 95% prediction accuracy.

In another embodiment of this aspect, the determination achieves agreater than 95% specificity and a greater than 95% sensitivity.

In another embodiment of this aspect, the measurement items selectedfrom the ADOS-G first module consist of: Frequency of VocalizationDirected to Others (A2); Unusual Eye Contact (B1); Responsive SocialSmile (B2); Shared Enjoyment in Interaction (B5); Showing (B9);Spontaneous Initiation of Joint Attention (B10); Functional Play withObjects (C1); and Imagination/Creativity (C2).

In another aspect, provided herein is a non-transitory computer-readablemedium comprising program code for diagnosing a disorder, which programcode, when executed, determines whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality: (a) comprises a set of specificbehaviors and measurements thereof identified after machine learninganalysis on the Autism Diagnostic Observation Schedule-Generic (ADOS-G)first module, (b) does not include measurement items based on the“response to name” activity of the ADOS-G first module, or (c) does notinclude measurement items based on the “response to joint attention”activity of the ADO S-G first module.

In another aspect, provided herein is a custom computing apparatus fordiagnosing a disorder, comprising: a processor; a memory coupled to theprocessor; a storage medium in communication with the memory and theprocessor, the storage medium containing a set of processor executableinstructions that, when executed by the processor configure the customcomputing apparatus to determine whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality: (a) comprises a set of specificbehaviors and measurements thereof identified after machine learninganalysis on the Autism Diagnostic Observation Schedule-Generic (ADOS-G)first module, (b) does not include measurement items based on the“response to name” activity of the ADOS-G first module, or (c) does notinclude measurement items based on the “response to joint attention”activity of the ADOS-G first module.

In another aspect, provided herein is a method for diagnosing adisorder, comprising determining whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality comprises a set of questionsdirected at a parent or other caregiver that are geared towardsmeasurement of specific behaviors learned from machine learning analysisof the Autism Diagnostic Interview-Revised (ADI-R) exam, and thedetermination is performed by a computer suitably programmed therefor.

In one embodiment of this aspect, the method further comprises takingthe plurality of measurements from the subject.

In another embodiment of this aspect, the plurality consists of 7measurement questions selected from the ADI-R exam.

In another embodiment of this aspect, the plurality consists essentiallyof measurements questions selected from the ADI-R exam.

In another embodiment of this aspect, the multivariate mathematicalalgorithm comprises alternating decision tree (ADTree).

In another embodiment of this aspect, the determination achieves agreater than about 95% prediction accuracy.

In another embodiment of this aspect, the determination achieves agreater than 95% specificity and a greater than 95% sensitivity.

In another embodiment of this aspect, the measurement questions selectedfrom the ADI-R exam consist of: Comprehension of simple language: answermost abnormal between 4 and 5 (comps15); Reciprocal conversation (withinsubject's level of language): answer if ever (when verbal) (conver5);Imaginative play: answer most abnormal between 4 and 5 (plays);Imaginative play with peers: answer most abnormal between 4 and 5(peerp15); Direct gaze: answer most abnormal between 4 and 5 (gazes);Group play with peers: answer most abnormal between 4 and 5 (grplay5);and Age when abnormality first evident (ageabn).

In another aspect, provided herein is a non-transitory computer-readablemedium comprising program code for diagnosing a disorder, which programcode, when executed, determines whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality a set of questions directed at aparent or other caregiver that are geared towards measurement ofspecific behaviors learned from machine learning analysis of the AutismDiagnostic Interview-Revised (ADI-R) exam.

In another aspect, provided herein is a custom computing apparatus fordiagnosing a disorder, comprising: a processor; a memory coupled to theprocessor; a storage medium in communication with the memory and theprocessor, the storage medium containing a set of processor executableinstructions that, when executed by the processor configure the customcomputing apparatus to determine whether a subject suffers from thedisorder with a multivariate mathematical algorithm taking a pluralityof measurements as input, the plurality comprises a set of questionsdirected at a parent or other caregiver that are geared towardsmeasurement of specific behaviors learned from machine learning analysisof the Autism Diagnostic Interview-Revised (ADI-R) exam.

In another aspect, provided herein is a method of diagnosing an autismspectrum disorder in a subject, the method comprising: scoring thesubject's behavior; analyzing results of the scoring with a diagnostictool to generate a final score, wherein the diagnostic tool is generatedby applying artificial intelligence to an instrument for diagnosis ofthe autism spectrum disorder; and providing an indicator as to whetherthe subject has the autism spectrum disorder based on the final scoregenerated by the analyzing step.

In one embodiment of this aspect, the instrument is a caregiver-directedquestionnaire, and wherein the step of scoring the subject's behaviorconsists of: scoring the subject's understanding of basic language;scoring the subject's use of back-and-forth conversation; scoring thesubject's level of imaginative or pretend play; scoring the subject'slevel of imaginative or pretend play with peers; scoring the subject'suse of eye contact; scoring the subject's behavior in peer groups; andscoring the subject's age when abnormality first recognized.

In another embodiment of this aspect, the subject's understanding ofbasic language is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject who in response to a request can place anobject, other than something to be used by himself/herself, in a newlocation in a different room, wherein the score of 1 corresponds with asubject who in response to a request can usually get an object, otherthan something for herself/himself from a different room, but usuallycannot perform a new task with the object such as put it in a new place,wherein the score of 2 corresponds with a subject who understands morethan 50 words, including names of friends and family, names of actionfigures and dolls, names of food items, but does not meet criteria forthe previous two answers, wherein the score of 3 corresponds with asubject who understands fewer than 50 words, but some comprehension of“yes” and “no” and names of a favorite objects, foods, people, and alsowords within daily routines, wherein the score of 4 corresponds with asubject who has little or no understanding of words, and wherein thescore of 8 corresponds with a subject whose understanding of basiclanguage is not applicable.

In another embodiment of this aspect, the subject's back-and-forthconversation is scored on a scale from 0 to 8, wherein the score of 1corresponds with a subject for whom conversation flows, with the subjectand another person both contributing to an ongoing dialogue, wherein thescore of 2 corresponds with a subject who exhibits occasionalback-and-forth conversation, but limited in flexibility or topics,wherein the score of 3 corresponds with a subject who exhibits little orno back-and-forth conversation, wherein the subject has difficultybuilding a conversation, wherein the subject fails to follow aconversation topic, and wherein the subject may ask or answer questionsbut not as part of a dialogue, wherein the score of 4 corresponds with asubject who rarely speaks or initiates conversation, and wherein thescore of 8 corresponds with a subject for whom level of back-and-forthconversation is not applicable or cannot be scored.

In another embodiment of this aspect, the subject's level of imaginativeor pretend play is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject exhibiting a variety of imagination andpretend play, including use of toys to engage in play activity, whereinthe score of 1 corresponds with a subject exhibiting some imaginationand pretend play, including pretending with toys, but limited in varietyor frequency, wherein the score of 2 corresponds with a subjectexhibiting occasional pretending or highly repetitive pretend play, oronly play that has been taught by others, wherein the score of 3corresponds with a subject showing no pretend play, and wherein thescore of 8 corresponds with a subject whose level of imaginative orpretend play is not applicable.

In another embodiment of this aspect, the subject's level of imaginativeor pretend play with peers is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who actively participates inimaginative play with other children in which the subject leads andfollows another child in pretend activities, wherein the score of 1corresponds with a subject who exhibits some participation in pretendplay with another child, but not truly back-and-forth, or level ofpretending/imagination is limited in variety, wherein the score of 2corresponds with a subject who exhibits some play with other children,but little or no pretending, wherein the score of 3 corresponds with asubject who engages in no play with other children or no pretend playwhen alone, and wherein the score of 8 corresponds with the subject'slevel of imaginative or pretend play with peers is not applicable.

In another embodiment of this aspect, the subject's use of eye contactis scored on a scale from 0 to 8, wherein the score of 0 correspondswith a subject for whom normal eye contact is used to communicate acrossa range of situations and people, wherein the score of 1 correspondswith a subject who makes normal eye contact, but briefly orinconsistently during social interactions, wherein the score of 2corresponds with a subject who makes uncertain/occasional direct eyecontact, or eye contact rarely used during social interactions, whereinthe score of 3 corresponds with a subject who exhibits unusual or odduse of eye contact, and wherein the score of 8 correspond with a subjectwhose use of eye contact is not applicable or scorable.

In another embodiment of this aspect, the subject's level of playbehavior in peer groups is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who actively seeks and playstogether with peers in several different groups in a variety ofactivities or situations, wherein the score of 1 corresponds with asubject who exhibits some play with peers, but tends not to initiate, ortends to be inflexible in the games played, wherein the score of 2corresponds with a subject who enjoys parallel active play, but littleor no cooperative play, wherein the score of 3 corresponds with asubject who seeks no play that involves participation in groups of otherchildren, though may chase or play catch, and wherein the score of 8corresponds with the subject's level of imaginative or pretend play withpeers is not applicable.

In another embodiment of this aspect, the subject's age when abnormalityfirst recognized is scored on a scale from 0 to 4, wherein the score of0 corresponds with a subject for whom development in the first 3 yearsof life has been or was clearly normal in quality and within normallimits for social, language, and physical milestones, and wherein thesubject exhibits no behavioral problems that might indicatedevelopmental delay, wherein the score of 1 corresponds with a subjectfor whom development is potentially normal during first 3 years, butuncertainty because of some differences in behavior or level of skillsin comparison to children of the same age, wherein the score of 2corresponds with a subject for whom development has been or was probablyabnormal by or before the age of 3 years, as indicated by developmentaldelay, but milder and not a significant departure from normaldevelopment, wherein the score of 3 indicates that development has beenor was clearly abnormal during the first 3 years, but not obvious asautism, and wherein the score of 4 indicates that the subject'sdevelopment has been or was clearly abnormal during the first 3 yearsand quality of behavior, social relationships, and communications appearto match behaviors consistent with autism.

In another embodiment of this aspect, the instrument is a set ofquestions that correspond to an observation of the subject in a video,video conference or in person, and wherein the step of scoring thesubject's behavior consists of: scoring the subject's tendency to directsounds, words or other vocalizations to others; scoring the subject'suse of eye contact; scoring the subject's tendency to smile in responseto social queues; scoring the subject's shared enjoyment in interaction;scoring the subject's tendency to show objects to another person;scoring the subject's tendency to initiate joint attention; scoring thesubject's level of appropriate play with toys or other objects; andscoring the subject's level of imagination/creativity.

In another embodiment of this aspect, the subject's tendency to directsounds, words or other vocalizations to others is scored on a scale from0 to 8, wherein the score of 0 corresponds with a subject who directssounds, words or other vocalizations to a caregiver or to otherindividuals in a variety of contexts and who chats or uses sounds to befriendly, express interest, and/or to make needs known, wherein thescore of 1 corresponds with a subject who directs sounds, words or othervocalizations to a caregiver or to other individuals regularly in onecontext, or directs vocalizations to caregiver or other individualsirregularly across a variety of situations/contexts, wherein the scoreof 2 corresponds with a subject who occasionally vocalizes to acaregiver or other individuals inconsistently in a limited number ofcontexts, possibly including whining or crying due to frustration,wherein the score of 3 corresponds with a subject who almost nevervocalizes or vocalizations never appear to be directed to caregiver orother individuals in the observation of the subject in a video, videoconference or in person, and wherein the score of 8 corresponds with asubject whose tendency to direct sounds, words or other vocalizations toothers is not applicable.

In another embodiment of this aspect, the subject's use of eye contactis scored on a scale from 0 to 8, wherein the score of 0 correspondswith a subject who makes normal eye contact, wherein the score of 2corresponds with a subject who has some irregular or unusual use of eyecontact to initiate, terminate, or regulate social interaction, andwherein the score of 8 corresponds with a subject whose use of eyecontact is not applicable or scorable.

In another embodiment of this aspect, the subject's tendency to smile inresponse to social queues is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who smiles immediately in responseto smiles by the caregiver or other individuals in the observation ofthe subject in a video, video conference or in person and with a subjectwho can switch from not smiling to smiling without being asked to smile,wherein the score of 1 corresponds with a subject who delays, onlysmiles partially, smiles only after repeated smiles by caregiver orother individuals in the observation of the subject in a video, videoconference or in person, or smiles only when asked, wherein the score of2 corresponds with a subject who smiles fully or partially at thecaregiver or other individuals only after being tickled, or only afterbeing prompted by repeated attempts which may include using a toy orother object, wherein the score of 3 corresponds with a subject who doesnot smile in response to another person, and wherein the score of 8corresponds with a subject whose tendency to smile in response to socialqueues is not applicable or cannot be scored.

In another embodiment of this aspect, the subject's shared enjoyment ininteraction is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject who shows clear and appropriate happinesswith the caregiver or other individuals during two or more activities,wherein the score of 1 corresponds with a subject who shows somewhatinconsistent signs of happiness with the caregiver or other individualsduring more than one activity, or only shows signs of happiness with thecaregiver or others involved during one interaction, wherein the scoreof 2 corresponds with a subject who shows little or no signs ofhappiness in interaction with the caregiver or others in the observationof the subject in a video, video conference or in person although mayexhibit signs of happiness when playing alone, wherein the score of 8corresponds with a subject whose shared enjoyment in interaction is notapplicable or cannot be scored.

In another embodiment of this aspect, the subject's tendency to showobjects to another person is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who spontaneously shows toys orobjects at various times during the observation of the subject in avideo, video conference or in person by holding them up or putting themin front of others and using eye contact with or without vocalization,wherein the score of 1 corresponds with a subject who shows toys orobjects partially or inconsistently, wherein the score of 2 correspondswith a subject who does not show objects to another person, and whereinthe score of 8 corresponds with a subject whose tendency to show objectsto another person is not applicable or cannot be evaluated.

In another embodiment of this aspect, the subject's tendency to initiatejoint attention is scored on a scale from 0 to 2, wherein the score of 0corresponds with a subject who uses normal eye contact to reference anobject that is out of reach by looking back-and-forth between thecaregiver or other person and the object, wherein eye contact may beused with pointing and/or vocalization, wherein the score of 1corresponds with a subject who partially references an object that isout of reach, wherein the subject may spontaneously look and point tothe object and/or vocalize, but does not use eye contact to get theattention of another person and then look at or point to the examiner orthe parent/caregiver, but not look back at the object, and wherein thescore of 2 corresponds with a subject that does not attempt to try toget another person's attention to reference an object that is out ofreach.

In another embodiment of this aspect, the subject's level of appropriateplay with toys or other objects is scored on a scale from 0 to 8,wherein the score of 0 corresponds with a subject who independentlyplays with a variety of toys in a conventional manner, includingappropriate play with action figures or dolls, wherein the score of 1corresponds with a subject who plays appropriately with some toys butnot always, wherein the score of 2 corresponds with a subject who playswith only one toy or one type of toy despite there being others aroundto play with, or only imitates others when playing with a toy, whereinthe score of 3 corresponds with a subject who does not play with toys orplays with toys in an inappropriate, stereotyped, or repetitive way, andwherein the score of 8 corresponds with a subject whose level ofappropriate play with toys or other objects is not applicable or cannotbe scored.

In another embodiment of this aspect, the subject'simagination/creativity is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who pretends that a doll or othertoy is something else during an imaginative play scenario, wherein thescore of 1 corresponds with a subject who may independently play pretendwith a doll or other object but with limited creativity or variation,wherein the score of 2 corresponds with a subject who only imitates thepretend play after watching a caregiver or other individual(s), and doesnot initiate pretend play on own, wherein the score of 3 correspondswith a subject who does not exhibit pretend play, and wherein the scoreof 8 corresponds with a subject for whom the subject's level ofimagination/creativity is not applicable or cannot be scored.

In another aspect, provided herein is a system of diagnosing an autismspectrum disorder in a subject, the system comprising: a scoring systemfor scoring the subject's behavior; an analysis system for analyzingresults of the scoring with a diagnostic tool to generate a final score,wherein the diagnostic tool is generated by applying artificialintelligence to an instrument for diagnosis of the autism spectrumdisorder; and an indicator system for indicating whether the subject hasthe autism spectrum disorder based on the final score generated by theanalyzing step.

In one embodiment of this aspect, the instrument is a caregiver-directedquestionnaire, and wherein the scoring system consists of: a system forscoring the subject's understanding of basic language; a system forscoring the subject's use of back-and-forth conversation; a system forscoring the subject's level of imaginative or pretend play; a system forscoring the subject's level of imaginative or pretend play with peers; asystem for scoring the subject's use of eye contact; a system forscoring the subject's behavior in peer groups; and a system for scoringthe subject's age when abnormality first recognized.

In another embodiment of this aspect, the subject's understanding ofbasic language is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject who in response to a request can place anobject, other than something to be used by himself/herself, in a newlocation in a different room, wherein the score of 1 corresponds with asubject who in response to a request can usually get an object, otherthan something for herself/himself from a different room, but usuallycannot perform a new task with the object such as put it in a new place,wherein the score of 2 corresponds with a subject who understands morethan 50 words, including names of friends and family, names of actionfigures and dolls, names of food items, but does not meet criteria forthe previous two answers, wherein the score of 3 corresponds with asubject who understands fewer than 50 words, but some comprehension of“yes” and “no” and names of a favorite objects, foods, people, and alsowords within daily routines, wherein the score of 4 corresponds with asubject who has little or no understanding of words, and wherein thescore of 8 corresponds with a subject whose understanding of basiclanguage is not applicable.

In another embodiment of this aspect, the subject's back-and-forthconversation is scored on a scale from 0 to 8, wherein the score of 1corresponds with a subject for whom conversation flows, with the subjectand another person both contributing to an ongoing dialogue, wherein thescore of 2 corresponds with a subject who exhibits occasionalback-and-forth conversation, but limited in flexibility or topics,wherein the score of 3 corresponds with a subject who exhibits little orno back-and-forth conversation, wherein the subject has difficultybuilding a conversation, wherein the subject fails to follow aconversation topic, and wherein the subject may ask or answer questionsbut not as part of a dialogue, wherein the score of 4 corresponds with asubject who rarely speaks or initiates conversation, and wherein thescore of 8 corresponds with a subject for whom level of back-and-forthconversation is not applicable or cannot be scored.

In another embodiment of this aspect, the subject's level of imaginativeor pretend play is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject exhibiting a variety of imagination andpretend play, including use of toys to engage in play activity, whereinthe score of 1 corresponds with a subject exhibiting some imaginationand pretend play, including pretending with toys, but limited in varietyor frequency, wherein the score of 2 corresponds with a subjectexhibiting occasional pretending or highly repetitive pretend play, oronly play that has been taught by others, wherein the score of 3corresponds with a subject showing no pretend play, and wherein thescore of 8 corresponds with a subject whose level of imaginative orpretend play is not applicable.

In another embodiment of this aspect, the subject's level of imaginativeor pretend play with peers is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who actively participates inimaginative play with other children in which the subject leads andfollows another child in pretend activities, wherein the score of 1corresponds with a subject who exhibits some participation in pretendplay with another child, but not truly back-and-forth, or level ofpretending/imagination is limited in variety, wherein the score of 2corresponds with a subject who exhibits some play with other children,but little or no pretending, wherein the score of 3 corresponds with asubject who engages in no play with other children or no pretend playwhen alone, and wherein the score of 8 corresponds with the subject'slevel of imaginative or pretend play with peers is not applicable.

In another embodiment of this aspect, the subject's use of eye contactis scored on a scale from 0 to 8, wherein the score of 0 correspondswith a subject for whom normal eye contact is used to communicate acrossa range of situations and people, wherein the score of 1 correspondswith a subject who makes normal eye contact, but briefly orinconsistently during social interactions, wherein the score of 2corresponds with a subject who makes uncertain/occasional direct eyecontact, or eye contact rarely used during social interactions, whereinthe score of 3 corresponds with a subject who exhibits unusual or odduse of eye contact, and wherein the score of 8 correspond with a subjectwhose use of eye contact is not applicable or scorable.

In another embodiment of this aspect, the subject's level of playbehavior in peer groups is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who actively seeks and playstogether with peers in several different groups in a variety ofactivities or situations, wherein the score of 1 corresponds with asubject who exhibits some play with peers, but tends not to initiate, ortends to be inflexible in the games played, wherein the score of 2corresponds with a subject who enjoys parallel active play, but littleor no cooperative play, wherein the score of 3 corresponds with asubject who seeks no play that involves participation in groups of otherchildren, though may chase or play catch, and wherein the score of 8corresponds with the subject's level of imaginative or pretend play withpeers is not applicable.

In another embodiment of this aspect, the subject's age when abnormalityfirst recognized is scored on a scale from 0 to 4, wherein the score of0 corresponds with a subject for whom development in the first 3 yearsof life has been or was clearly normal in quality and within normallimits for social, language, and physical milestones, and wherein thesubject exhibits no behavioral problems that might indicatedevelopmental delay, wherein the score of 1 corresponds with a subjectfor whom development is potentially normal during first 3 years, butuncertainty because of some differences in behavior or level of skillsin comparison to children of the same age, wherein the score of 2corresponds with a subject for whom development has been or was probablyabnormal by or before the age of 3 years, as indicated by developmentaldelay, but milder and not a significant departure from normaldevelopment, wherein the score of 3 indicates that development has beenor was clearly abnormal during the first 3 years, but not obvious asautism, and wherein the score of 4 indicates that the subject'sdevelopment has been or was clearly abnormal during the first 3 yearsand quality of behavior, social relationships, and communications appearto match behaviors consistent with autism.

In another embodiment of this aspect, the instrument is a set ofquestions that correspond to an observation of the subject in a video,video conference or in person, and wherein the scoring system consistsof: a system for scoring the subject's tendency to direct sounds, wordsor other vocalizations to others; a system for scoring the subject's useof eye contact; a system for scoring the subject's tendency to smile inresponse to social queues; a system for scoring the subject's sharedenjoyment in interaction; a system for scoring the subject's tendency toshow objects to another person; a system for scoring the subject'stendency to initiate joint attention; a system for scoring the subject'slevel of appropriate play with toys or other objects; and a system forscoring the subject's level of imagination/creativity.

In another embodiment of this aspect, the subject's tendency to directsounds, words or other vocalizations to others is scored on a scale from0 to 8, wherein the score of 0 corresponds with a subject who directssounds, words or other vocalizations to a caregiver or to otherindividuals in a variety of contexts and who chats or uses sounds to befriendly, express interest, and/or to make needs known, wherein thescore of 1 corresponds with a subject who directs sounds, words or othervocalizations to a caregiver or to other individuals regularly in onecontext, or directs vocalizations to caregiver or other individualsirregularly across a variety of situations/contexts, wherein the scoreof 2 corresponds with a subject who occasionally vocalizes to acaregiver or other individuals inconsistently in a limited number ofcontexts, possibly including whining or crying due to frustration,wherein the score of 3 corresponds with a subject who almost nevervocalizes or vocalizations never appear to be directed to caregiver orother individuals in the observation of the subject in a video, videoconference or in person, and wherein the score of 8 corresponds with asubject whose tendency to direct sounds, words or other vocalizations toothers is not applicable.

In another embodiment of this aspect, the subject's use of eye contactis scored on a scale from 0 to 8, wherein the score of 0 correspondswith a subject who makes normal eye contact, wherein the score of 2corresponds with a subject who has some irregular or unusual use of eyecontact to initiate, terminate, or regulate social interaction, andwherein the score of 8 corresponds with a subject whose use of eyecontact is not applicable or scorable.

In another embodiment of this aspect, the subject's tendency to smile inresponse to social queues is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who smiles immediately in responseto smiles by the caregiver or other individuals in the observation ofthe subject in a video, video conference or in person and with a subjectwho can switch from not smiling to smiling without being asked to smile,wherein the score of 1 corresponds with a subject who delays, onlysmiles partially, smiles only after repeated smiles by caregiver orother individuals in the observation of the subject in a video, videoconference or in person, or smiles only when asked, wherein the score of2 corresponds with a subject who smiles fully or partially at thecaregiver or other individuals only after being tickled, or only afterbeing prompted by repeated attempts which may include using a toy orother object, wherein the score of 3 corresponds with a subject who doesnot smile in response to another person, and wherein the score of 8corresponds with a subject whose tendency to smile in response to socialqueues is not applicable or cannot be scored.

In another embodiment of this aspect, the subject's shared enjoyment ininteraction is scored on a scale from 0 to 8, wherein the score of 0corresponds with a subject who shows clear and appropriate happinesswith the caregiver or other individuals during two or more activities,wherein the score of 1 corresponds with a subject who shows somewhatinconsistent signs of happiness with the caregiver or other individualsduring more than one activity, or only shows signs of happiness with thecaregiver or others involved during one interaction, wherein the scoreof 2 corresponds with a subject who shows little or no signs ofhappiness in interaction with the caregiver or others in the observationof the subject in a video, video conference or in person although mayexhibit signs of happiness when playing alone, wherein the score of 8corresponds with a subject whose shared enjoyment in interaction is notapplicable or cannot be scored.

In another embodiment of this aspect, the subject's tendency to showobjects to another person is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who spontaneously shows toys orobjects at various times during the observation of the subject in avideo, video conference or in person by holding them up or putting themin front of others and using eye contact with or without vocalization,wherein the score of 1 corresponds with a subject who shows toys orobjects partially or inconsistently, wherein the score of 2 correspondswith a subject who does not show objects to another person, and whereinthe score of 8 corresponds with a subject whose tendency to show objectsto another person is not applicable or cannot be evaluated.

In another embodiment of this aspect, the subject's tendency to initiatejoint attention is scored on a scale from 0 to 2, wherein the score of 0corresponds with a subject who uses normal eye contact to reference anobject that is out of reach by looking back-and-forth between thecaregiver or other person and the object, wherein eye contact may beused with pointing and/or vocalization, wherein the score of 1corresponds with a subject who partially references an object that isout of reach, wherein the subject may spontaneously look and point tothe object and/or vocalize, but does not use eye contact to get theattention of another person and then look at or point to the examiner orthe parent/caregiver, but not look back at the object, and wherein thescore of 2 corresponds with a subject that does not attempt to try toget another person's attention to reference an object that is out ofreach.

In another embodiment of this aspect, the subject's level of appropriateplay with toys or other objects is scored on a scale from 0 to 8,wherein the score of 0 corresponds with a subject who independentlyplays with a variety of toys in a conventional manner, includingappropriate play with action figures or dolls, wherein the score of 1corresponds with a subject who plays appropriately with some toys butnot always, wherein the score of 2 corresponds with a subject who playswith only one toy or one type of toy despite there being others aroundto play with, or only imitates others when playing with a toy, whereinthe score of 3 corresponds with a subject who does not play with toys orplays with toys in an inappropriate, stereotyped, or repetitive way, andwherein the score of 8 corresponds with a subject whose level ofappropriate play with toys or other objects is not applicable or cannotbe scored.

In another embodiment of this aspect, the subject'simagination/creativity is scored on a scale from 0 to 8, wherein thescore of 0 corresponds with a subject who pretends that a doll or othertoy is something else during an imaginative play scenario, wherein thescore of 1 corresponds with a subject who may independently play pretendwith a doll or other object but with limited creativity or variation,wherein the score of 2 corresponds with a subject who only imitates thepretend play after watching a caregiver or other individual(s), and doesnot initiate pretend play on own, wherein the score of 3 correspondswith a subject who does not exhibit pretend play, and wherein the scoreof 8 corresponds with a subject for whom the subject's level ofimagination/creativity is not applicable or cannot be scored.

In another aspect, provided herein is a computer implemented method ofgenerating a diagnostic tool by applying artificial intelligence to aninstrument for diagnosis of a disorder, wherein the instrument comprisesa full set of diagnostic items, the computer implemented methodcomprising: on a computer system having one or more processors and amemory storing one or more computer programs for execution by the one ormore processors, the one or more computer programs includinginstructions for: scoring the subject's behavior; analyzing results ofthe scoring with a diagnostic tool to generate a final score, whereinthe diagnostic tool is generated by applying artificial intelligence toan instrument for diagnosis of the autism spectrum disorder; andproviding an indicator as to whether the subject has the autism spectrumdisorder based on the final score generated by the analyzing step.

In another aspect, provided herein is a computer system of diagnosing anautism spectrum disorder in a subject, the system comprising: one ormore processors; and memory to store: one or more computer programs, theone or more computer programs comprising instructions for: scoring thesubject's behavior; analyzing results of the scoring with a diagnostictool to generate a final score, wherein the diagnostic tool is generatedby applying artificial intelligence to an instrument for diagnosis ofthe autism spectrum disorder; and providing an indicator as to whetherthe subject has the autism spectrum disorder based on the final scoregenerated by the analyzing step.

In another aspect, provided herein is a non-transitory computer-readablestorage medium storing one or more computer programs configured to beexecuted by one or more processing units at a computer comprisinginstructions for: scoring a subject's behavior; analyzing results of thescoring with a diagnostic tool to generate a final score, wherein thediagnostic tool is generated by applying artificial intelligence to aninstrument for diagnosis of the autism spectrum disorder; and providingan indicator as to whether the subject has an autism spectrum disorderbased on the final score generated by the analyzing step.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into thisspecification, illustrate one or more exemplary embodiments of theinventions disclosed herein and, together with the detailed description,serve to explain the principles and exemplary implementations of theseinventions. One of skill in the art will understand that the drawingsare illustrative only, and that what is depicted therein may be adaptedbased on the text of the specification and the spirit and scope of theteachings herein.

In the drawings, where like reference numerals refer to like referencein the specification:

FIG. 1 is a chart showing performance of all 15 machine learningalgorithms evaluated for classifying autism cases versus controls(ADI-R);

FIG. 2 shows an example of a decision tree for a behavioral classifiergenerated by the Alternating Decision Tree (ADTree) algorithm (ADI-R);

FIG. 3 is a chart showing decision tree scores and classification ofcases with and without autism (ADI-R);

FIG. 4 is a chart showing performance of all 15 machine learningalgorithms evaluated for classifying autism cases versus controls(ADOS);

FIG. 5 shows an example of a decision tree for a video-based classifier(VBC);

FIG. 6 is a chart showing validation and coverage (ADI-R);

FIG. 7 shows an example of a decision tree for a classifier generated bythe Alternating Decision Tree (ADTree) algorithm when applied toupsampling the controls;

FIG. 8 is a block diagram demonstrating the input of data, analysis ofdata using machine learning (ML) algorithm(s), cross validation (such as10-fold cross validation), classification of the data into two broadcategories and goal of maintaining sensitivity and specificity;

FIG. 9 shows an example of the use of social networks with the presentinvention;

FIG. 10 is another example of the use of social networks with thepresent invention;

FIG. 11 displays survey results;

FIG. 12 shows an example of a diagnostics screen from a social network;

FIG. 13 is a photograph of an example of materials used for an ADOSModule;

FIG. 14 shows an example of an introduction screen for The AutworksVideo Project at Harvard Medical School;

FIG. 15 is a flow chart associated with a video screening method;

FIG. 16 is a chart demonstrating high inter-rater reliability;

FIG. 17 is a chart demonstrating the combination of inter-rater resultsfor maximum performance;

FIG. 18 is yet another example of the use of social networks with thepresent invention;

FIG. 19 shows an example of the use of YouTube with the presentinvention;

FIG. 20 shows an example of a parent and care provider portal;

FIG. 21 shows an example of a portal that prompts the user for homevideo;

FIG. 22 shows an example of workflow associated with a video screeningmethod;

FIG. 23 shows an example of a query screen associated with a Watch andScore Home Videos module;

FIG. 24 shows an example of a Prescreening Clinician Report;

FIG. 25 is another example of a Prescreening Clinician Report;

FIG. 26 shows an example of a Prescreening Caregiver Report;

FIG. 27 shows an example of a parent-/caregiver-directed classifier;

FIG. 28 shows an example of a pipeline for generating a classificationscore using the caregiver-directed classifier (CDC);

FIG. 29 shows an example of a pipeline for generating a classificationscore using the video-based classifier (VBC);

FIG. 30 shows an example of a machine learning classification method forcreating Reduced Testing Procedures (RTPs) that can be embedded intomobilized frameworks for rapid testing outside of clinical sites;

FIG. 31 shows an example of infrastructure for data hosting and reportgeneration using the CDC and VBC;

FIG. 32 shows an example of an input system prompting the user to enterpatient information;

FIG. 33 shows an example of an input system prompting the user toupload, change or view a video;

FIG. 34 shows an example of a video;

FIG. 35 shows an example of video analysis web framework;

FIG. 36 shows an example of an upload process for a smartdevice-deployed tool, designed as a machine-specific tool for rapidcapture and delivery of home videos suitable for a video-basedclassifier;

FIG. 37 is a block diagram including an instrument, a diagnostic tool, acomputer system, a processor, a memory and a computer program;

FIG. 38 shows an example of workflow for the CDC; and

FIG. 39 shows an example of workflow for the VBC.

DETAILED DESCRIPTION

It should be understood that this invention is not limited to theparticular methodology, protocols, etc., described herein and as suchmay vary. The terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.

As used herein and in the claims, the singular forms include the pluralreference and vice versa unless the context clearly indicates otherwise.Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities used herein should be understood asmodified in all instances by the term “about.”

All publications identified are expressly incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood to one of ordinaryskill in the art to which this invention pertains. Although any knownmethods, devices, and materials may be used in the practice or testingof the invention, the methods, devices, and materials in this regard aredescribed herein.

Some Selected Definitions

Unless stated otherwise, or implicit from context, the following termsand phrases include the meanings provided below. Unless explicitlystated otherwise, or apparent from context, the terms and phrases belowdo not exclude the meaning that the term or phrase has acquired in theart to which it pertains. The definitions are provided to aid indescribing particular embodiments of the aspects described herein, andare not intended to limit the claimed invention, because the scope ofthe invention is limited only by the claims. Further, unless otherwiserequired by context, singular terms shall include pluralities and pluralterms shall include the singular.

As used herein the term “comprising” or “comprises” is used in referenceto compositions, methods, and respective component(s) thereof, that areessential to the invention, yet open to the inclusion of unspecifiedelements, whether essential or not.

As used herein the term “consisting essentially of” refers to thoseelements required for a given embodiment. The term permits the presenceof additional elements that do not materially affect the basic and novelor functional characteristic(s) of that embodiment of the invention.

The term “consisting of” refers to compositions, methods, and respectivecomponents thereof as described herein, which are exclusive of anyelement not recited in that description of the embodiment.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities used herein should be understood asmodified in all instances by the term “about.” The term “about” whenused in connection with percentages may mean±1%.

The singular terms “a,” “an,” and “the” include plural referents unlesscontext clearly indicates otherwise. Similarly, the word “or” isintended to include “and” unless the context clearly indicatesotherwise. Thus for example, references to “the method” includes one ormore methods, and/or steps of the type described herein and/or whichwill become apparent to those persons skilled in the art upon readingthis disclosure and so forth.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of this disclosure,suitable methods and materials are described below. The term “comprises”means “includes.” The abbreviation, “e.g.” is derived from the Latinexempli gratia, and is used herein to indicate a non-limiting example.Thus, the abbreviation “e.g.” is synonymous with the term “for example.”

As used herein, a “subject” means a human or animal. Usually the animalis a vertebrate such as a primate, rodent, domestic animal or gameanimal. Primates include chimpanzees, cynomologous monkeys, spidermonkeys, and macaques, e.g., Rhesus. Rodents include mice, rats,woodchucks, ferrets, rabbits and hamsters. Domestic and game animalsinclude cows, horses, pigs, deer, bison, buffalo, feline species, e.g.,domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g.,chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.Patient or subject includes any subset of the foregoing, e.g., all ofthe above, but excluding one or more groups or species such as humans,primates or rodents. In certain embodiments of the aspects describedherein, the subject is a mammal, e.g., a primate, e.g., a human. Theterms, “patient” and “subject” are used interchangeably herein.

The present invention can use statistical classification techniquesincluding methods in artificial intelligence and machine learning, aswell as other statistical approaches including hierarchical clustering,methods of phylogenetic tree reconstruction including parsimony, maximumlikelihood, and distance optimality criteria, and pattern recognitionand data exploration approaches such as principle components analysis,correspondence analysis and similar methods, to identify a minimal setof explanatory behaviors/phenotypes/morphologies that can accuratelyindicate the presence or absence of a human disorder (principallyincluding autism).

To the extent not already indicated, it will be understood by those ofordinary skill in the art that any one of the various embodiments hereindescribed and illustrated may be further modified to incorporatefeatures shown in any of the other embodiments disclosed herein.

The following examples illustrate some embodiments and aspects of theinvention. It will be apparent to those skilled in the relevant art thatvarious modifications, additions, substitutions, and the like can beperformed without altering the spirit or scope of the invention, andsuch modifications and variations are encompassed within the scope ofthe invention as defined in the claims which follow. The followingexamples do not in any way limit the invention.

Part I: Use of Artificial Intelligence to Shorten the BehavioralDiagnosis of

Autism

Abstract

The Autism Diagnostic Interview-Revised (ADI-R) is one of the mostcommonly used instruments for behavioral diagnosis of autism. The examconsists of over 150 elements that must be addressed by a care providerand interviewer within a focused session that can last up to 2.5 hours.According to the present invention, machine learning techniques can beused to study the complete sets of answers to the ADI-R available at theAutism Genetic Research Exchange (AGRE) for 891 individuals diagnosedwith autism and 75 individuals who did not meet the criteria for autismdiagnosis. The analysis according to the invention showed that 7 of the152 items contained in the ADI-R were sufficient to diagnosis autismwith 99.9% statistical accuracy. The invention can include furthertesting of the accuracy of this 7-question classifier against completesets of answers from two independent sources, a collection of 1,654autistic individuals from the Simons Foundation and a collection of 322autistic individuals from the Boston Autism Consortium (AC). (Otherindependent sources can be used including but not limited to NationalDatabase for Autism Research, The Autism Genetic Research Exchange orany suitable repository of data.) In both cases, the classifierperformed with nearly 100% statistical accuracy, properly categorizingall but one of the individuals from these two resources who previouslyhad been diagnosed with autism through the standard ADI-R. Withincidence rates rising, the capacity to diagnose autism quickly andeffectively requires careful design of behavioral diagnostics. Theinvention is the first attempt to retrospectively analyze large datarepositories to derive a highly accurate, but significantly abbreviateddiagnostic instrument. According to the present invention, a completelynew diagnostic tool is created, which is designed to target elements,i.e., behaviors and morphology, that the present machine learningprocesses identify as vital to a diagnosis and, critically, an algorithmis created, which intelligently, i.e., numerically and statistically,combines the target elements to provide a disorder/non-disorderclassification. Such retrospective analyses provide valuablecontributions to the diagnosis process and help lead to faster screeningand earlier treatment of autistic individuals.

Summary

The incidence of autism has increased dramatically over recent years,making this mental disorder one of the greatest public health challengesof our time. The standard practice of diagnosis is strictly based onbehavioral characteristics, as the genome has largely proved intractablefor diagnostic purposes. Yet, the most commonly used behavioralinstruments take as much as 3 hours to administer by a trainedspecialist, contributing to the substantial delays in diagnosisexperienced by many children, who may go undiagnosed and untreated untilages beyond when behavioral therapy would have had more substantivepositive impacts. In the present study, the invention can use machinelearning techniques to analyze the answers to one of the most commonlyused behavioral instruments, the Autism Diagnostic Interview-Revised(ADI-R), to determine if the exam could be shortened without loss ofdiagnostic accuracy. Deploying an alternative decision tree learningalgorithm according to the invention, the total number of questions canbe successfully reduced from 93 to 7, a total reduction of 93%. Thisabbreviation came with almost no loss in the accuracy when compared tothe diagnosis provided by the full ADI-R in three independentcollections of data and over 2,800 autistic cases. Such a diagnostictool could have significant impact on the timeframe of diagnosis, makingit possible for more children to receive diagnosis and care early intheir development.

Introduction

Although autism is a genetic disease (Bailey, et al., “Autism as astrongly genetic disorder: evidence from a British twin study,” PsycholMed, 1995, 25(1):63-77), it is diagnosed through behavior. The clinicalpractice of diagnosis has been formalized through instruments containingquestions carefully designed to assess impairments in threedevelopmental domains: communication and social interactions, restrictedinterests and activities, and stereotypical behaviors. One of the mostwidely adopted instruments is the Autism Diagnostic Interview—Revised(ADI-R) (Lord, et al., “Autism Diagnostic Interview-Revised: a revisedversion of a diagnostic interview for caregivers of individuals withpossible pervasive developmental disorders,” J Autism Dev Disord, 1994,24(5):659-685). This exam contains 93 main questions and numeroussub-elements that sum to over 150 items. It is an interview-based examconducted by a trained individual who obtains information from aninformant, e.g., parent or caregiver. The exam is meant to inquire aboutindividuals with a mental age of at least two years, and due to thelarge number of questions in the exam, can take up to 2.5 hours tocomplete. While the instrument is highly reliable, consistent acrossexaminers (Cicchetti, et al., “Reliability of the ADI-R: multipleexaminers evaluate a single case,” Autism Dev Disord, 2008,38(4):764-770), and results in a rich understanding of the individualsuspected of having autism, its length can be prohibitive.

The practice of diagnosing autism varies widely in terms of standardsand timeframes. Children may wait as long as 13 months between initialscreening and diagnosis (Wiggins, et al., “Examination of the timebetween first evaluation and first autism spectrum diagnosis in apopulation-based sample,” Journal of developmental and behavioralpediatrics, IDBP 2006, 27(2 Suppl):S79-87). Similar studies have alsofound substantial delays between the time of first parental concern andactual diagnosis. Substantial delays in diagnosis are often seen infamilies with different racial and ethnic backgrounds, partly due tosocioeconomic status and cultural beliefs, for example, African Americanchildren spend more time in treatment before receiving an autismspectrum disorder (ASD) diagnosis (Bernier, et al., “Psychopathology,families, and culture: autism,” Child Adolesc Psychiatr Clin N Am, 2010,19(4):855-867). A shortened and readily accessible diagnostic exam couldimprove these statistics.

Significant attention has been paid to the design of abbreviatedscreening examinations that are meant to foster more rapid diagnosis,including the Autism Screening Questionnaire (ASQ, designed todiscriminate between PDD and non-PDD diagnoses (Berument, et al.,“Autism screening questionnaire: diagnostic validity,” Br J Psychiatry,1999, 175:444-451)), the Modified Checklist for Autism in Toddlers(MCHAT) (Robins, et al., “The Modified Checklist for Autism in Toddlers:an initial study investigating the early detection of autism andpervasive developmental disorders,” J Autism Dev Disord, 2001,31(2):131-144), and the Parents' Evaluation of Developmental Status(PEDS) (Pinto-Martin, et al., “Screening strategies for autism spectrumdisorders in pediatric primary care,” J Dev Behav Pediatr, 2008,29(5):345-350), to name a few. However, most of these have been adoptedfor basic screening rather than formal diagnosis, and are tools usedprior to administering the ADI-R or Autism Diagnostic ObservationSchedule (ADOS) (Lord, et al., “Autism diagnostic observation schedule:a standardized observation of communicative and social behavior,” JAutism Dev Disord, 1989, 19(2):185-212). While some pediatriciansconduct routine autism screenings during well-child visits, it has yetto become a universal practice (Gura, et al., “Autism spectrum disorderscreening in primary care,” J Dev Behav Pediatr, 2011, 32(1):48-51)leaving much of the burden on the parent or care provider. Parents oftenhesitate to take immediate action without a clinical assessment andformal diagnosis, furthering delays in the treatment of the childthrough behavioral therapy or other means (Howlin, “Children with Autismand Asperger's Syndrome: A Guide for Practitioners and Parents,”Chichester, UK: Wiley; 1998)(Pisula, “Parents of children with autism:review of current research,” Arch Psychiatry Psychother, 2003, 5:51-63).An exam that preserves the reliability of the ADI-R but that can beadministered in minutes rather than hours enables more rapid diagnosis,higher throughput, as well as timely and more impactful delivery oftherapy.

A direct way to test whether a reduction of the complexity of ADI-Rprovides the same level of accuracy as the full exam is to lookretrospectively at answers to the full ADI-R for a large set ofindividuals with autism. Many efforts to-date on shortening thebehavioral diagnosis of autism have leveraged clinical experience andcriteria established by the DSM-IV to prospectively design and test newinstruments. However, as a valuable byproduct of the widespread adoptionand use of ADI-R, researchers now have large digital repositories ofitem-level answers to each question coupled with the clinical diagnosisthat can be mined to test this question directly. According to theinvention, analytical strategies can be employed from the field ofmachine learning to retrospectively analyze the full ADI-R for over 800individuals with autism, with the aim centered on significantly reducingthe number of questions while preserving the classification given by thefull ADI-R.

Results

The invention may begin with ADI-R data from the Autism Genetic ResourceExchange (AGRE). After removing 24 questions that did not meet thestandards for inclusion, 129 questions and sub-questions from the fullADI-R data were left. The invention can compare the performance of 15different machine learning algorithms on these 129 attributes. Inaccordance with the invention, the Alternating Decision Tree (ADTree) isshown to perform the best in terms of both sensitivity and specificityof classification (FIG. 1), with perfect sensitivity of 1.0, a falsepositive rate (FPR) of 0.013, and overall accuracy of 99.90%. See Table1 for a summary of the 15 machine learning algorithms used in theanalysis.

FIG. 1 charts the performance of all 15 machine learning algorithmsevaluated for classifying autism cases versus controls. Receiveroperator curves mapping 1-specificity versus sensitivity for the 15different machine learning algorithms tested against the AutismDiagnostic Interview-Revised (ADI-R) data from the Autism GeneticResource Exchange (ACRE). The algorithm of the present inventionyielding a classifier with false positive rate closest to 0 and truepositive rate closest to 1, a perfect classifier, was identified. Thebest performing approach was the alternating decision tree (ADTree),followed by LADTree, PART, and FilteredClassifier. Table 1 summarizesthe 15 machine learning algorithms in more detail, and the resultingclassifier as a decision tree is depicted in FIG. 2. In FIG. 1, thex-axis ranges from 0 to 0.2 with increments of 0.05, and the y-axisranges from 0.98 to 1 with increments of 0.005.

Table 1 shows 15 machine learning algorithms used to analyze the AutismGenetic Resource Exchange ADI-R data. These algorithms were deployedusing the toolkit WEKA. The false positive rate (FPR) and true positiverate (TPR) are provided together with overall accuracy. The AlternatingDecision Tree (ADTree) performed with highest accuracy and was used forfurther analysis.

TABLE 1 Classifier Name Description FPR TPR Accuracy ADTree An ADTreecombines decision trees, 0.013 1.000 0.999 voted decision trees, andvoted decision stumps. This particular algorithm is based on boosting,which produces accurate predictions by combining a series of “weak”learners that together, can classify accurately (Freund, et al., “Thealternating decision tree learning algorithm,” In: Machine Learning:Proceedings of the Sixteenth International Conference 1999, 124- 133).BFTree The top node of the decision tree is the 0.053 0.991 0.988 onethat splits the data so that the maximum reduction of impurity(misclassified data) is achieved. This is called the “best” node, and itis expanded upon first (unlike in a C4.5 tree, for example, where nodesare expanded upon according to depth-first) (Shi, “Best-first DecisionTree Learning,” Master Thesis, The University of Waikato, 2007).ConjunctiveRule Within the ConjuctiveRule classifier is 0.080 0.9810.976 a conjunctive rule learner, which can predict for both numeric andnominal class labels. A rule consists of a series of antecedents joinedby “AND”s (Freund, et al., “Experiments with a new boosting algorithm,”In: Proceedings of the International Conference on Machine Learning:1996; San Francisco, Morgan Kautinann: 148-156). DecisionStump ADecisionStump classifier is a 0.107 0.985 0.978 single-level decisiontree with one node. The terminal nodes extend directly off of this node,so a classification is made based on a single attribute (Freund, et al.,“Experiments with a new boosting algorithm,” In: Proceedings of theInternational Conference on Machine Learning: 1996; San Francisco,Morgan Kautinann: 148-156). FilteredClassifier FilteredClassifier runsdata through an 0.040 0.993 0.991 arbitrary classifier after its beenrun through an arbitrary filter. Classifiers are built using trainingdata, and in this case, the filter is also built based on the trainingdata. This allows the user to skip the pre-processing steps associatedwith transforming the data (Hall, et al., “The WEKA Data MiningSoftware: An Update,” SIGKDD Explorations, 2009, 11(1):1). J48 J48 is aJava implementation of the C4.5 0.053 0.998 0.994 algorithm; itgenerates either an unpruned or a pruned C4.5 decision tree. C4.5 usesthe concept of information entropy to build trees from training data(Quinlan, “C4.5,” San Mateo: Morgan Kaufmann Publishers; 1993). J48graftThis class generates a grafted C4.5 0.200 1.000 0.984 decision tree thatcan either be pruned or unpruned. Grafting adds nodes to already createddecision trees to improve accuracy (Freund, et al., “The alternatingdecision tree learning algorithm,” In: Machine Learning: Proceedings ofthe Sixteenth International Conference 1999, 124- 133). JRip Thisclassifier is an optimized version 0.053 0.997 0.993 of IncrementalReduced Error Pruning, and implements a propositional learner, RIPPER(Repeated Incremental Pruning to Produce Error Reduction). It producesaccurate and “readable” rules (Cohen, “Fast Effective Rule Induction,”Twelfth International Conference on Machine Learning, 1995:115-123)LADTree LADTree produces a multi-class 0.027 1.000 0.998 alternatingdecision tree. It has the capability to have more than two class inputs.It uses the LogitBoost strategy, which performs additive logisticregression (Holmes, et al., “Multiclass alternating decision trees,”ECML, 2001:161-172) NNge Nearest neighbor algorithms define a 0.0801.000 0.994 distance function to separate classes. Using generalizedexemplars reduce the role of the distance function (relying too heavilyon the distance function can produce inaccurate results) by groupingclasses together (Martin, “Instance-Based learning: Nearest NeighborWith Generalization,” Hamilton, New Zealand.: University of Waikato;1995). OneR This algorithm finds association rules. It 0.093 0.996 0.989finds the one attribute that classifies instances so as to reduceprediction errors (Holte, “Very simple classification rules perform wellon most commonly used datasets,” Machine Learning: Proceedings of theSixteenth International Conference, 1993, 11:63-91).OrdinalClassClassifier This is a meta-classifier (meta- 0.053 0.9980.994 classifiers are like classifiers, but have added functionality)used to transform an ordinal class problem to a series of binary classproblems (Frank, et al., “A simple approach to ordinal prediction,” In:European Conference on Machine Learning; Freiburg, Germany, Springer-Verlag 2001: 145-156). PART A set of rules is generated using the 0.0400.996 0.993 “divide-and-conquer” strategy. From here, all instances inthe training data that are covered by this rule get removed and thisprocess is repeated until no instances remain (Frank, et al.,“Generating Accurate Rule Sets Without Global Optimization,” In: MachineLearning: Proceedings of the Fifteenth International Conference: 1998;San Francisco, CA, Morgan Kaufmann Publishers). Ridor This classifier isan implementation of 0.080 0.996 0.990 a Ripple-Down Rule Learner. Anexample of this is when the classifier picks a default rule (based onthe least weighted error), and creates exception cases stemming fromthis one (Gaines, et al., “Induction of Ripple-Down Rules Applied toModeling Large Databases,” J Intell Inf Syst, 1995, 5(3):211-228)SimpleCart Classification and regression trees are 0.053 0.993 0.990used to construct prediction models for data. They are made bypartitioning the data and fitting models to each partition (Breiman, etal., “Classification and Regression Trees,” Wadsworth InternationalGroup, Belmont, California, 1984).

Specifically, the ADTree classifier correctly classified all AGREindividuals previously labeled with a diagnosis of autism using the fullADI-R exam and misclassified only 1 control individual. The ADTreeclassifier itself was composed of only 7 questions from the 129 totalused in the analysis. These were ageabn, grplay5, conver5, peerp15,gaze5, play5, and comps15 (Table 1), and together represent a 95%reduction in the total number of elements overall.

Table 2 lists the seven attributes used in the ADTree model. Listed isthe number corresponding to the question in the full ADI-R instrument,the question code used by Autism Genetic Research Exchange (ACRE), abrief description of the question, and the number of classifiers of the15 tested in which the attribute appeared.

TABLE 2 Question Number Question Classifier on ADI-R Code Questionsubject Frequency 29 compsl5 Comprehension of 3 simple language: answermost abnormal between 4 and 5 35 conver5 Reciprocal 10 conversation(within subject's level of language): answer if ever (when verbal) 48play5 Imaginative play: 3 answer most abnormal between 4 and 5 49peerpl5 Imaginative play with 10 peers: answer most abnormal between 4and 5 50 gaze5 Direct gaze: answer 6 most abnormal between 4 and 5 64grplay5 Group play with 7 peers: answer most abnormal between 4 and 5 86ageabn Age when 14 abnormality first evident

The 7 questions formed the elements of a decision tree through which theclassification of “autism” or “not met” was derived (FIG. 2). Threequestions appeared more than once in the tree (ageabn, play5, andpeerp15), suggesting a slightly larger role in the classificationoutcome than the other 4 questions. Each question either increased ordecreased a running sum score called the ADTree score. A negative scoreresulted in a diagnosis of “autism” and a positive score yielded theclassification “not met.” The amplitude of the score provided a measureof confidence in classification outcome, with larger absolute valuesindicating higher confidence overall, as previously indicated in Freund(Freund, et al., “A decision-theoretic generalization of on-linelearning and an application to boosting,” Journal of Computer and SystemSciences, 1997, 55, 119-139). In the study, the vast majority of thescores were near or at the maximum for both the case and controlclasses, with comparably few individuals with intermediate values (FIG.3) indicating that the predictions made by the classifier were robustand well supported.

FIG. 2 depicts the official behavioral classifier generated by theAlternating Decision Tree (ADTree) algorithm. The ADTree was found toperform best out of 15 different machine learning approaches (FIG. 1,Table 1) and achieved nearly perfect sensitivity and specificity whendistinguishing autistic cases from controls. The resulting tree enablesone to follow each path originating from the top node, sum theprediction values and then use the sign to determine the class. In thiscase, a negative sum yielded the classification of “autism” while apositive sum yielded the classification of “not met.” Additionally, themagnitude of the sum is an indicator of prediction confidence.

FIG. 3 shows an example of decision tree scores and classification ofcases with and without autism. FIG. 3 includes the Alternating DecisionTree (ADTree) scores of individuals in both the AC and AGRE data setsversus their age in years. A majority of the ADTree scores are clusteredtowards greater magnitudes according to their respectiveclassifications, regardless of age. In this case, 7 subjects weremisclassified with autism, of which 5 had a previous diagnosis. All 7met criteria for autism via ADOS. The subjects ranged in age from 13months to 45 years. In FIG. 3, the x-axis ranges from 0 to 50 withincrements of 10, and the y-axis ranges from −12 to 8 with increments of2.

To independently validate the 7-question classifier, the invention canuse completed ADI-R score sheets from two repositories, the SimonsFoundation (SSC) and the Boston Autism consortium (AC) (Table 3).

Table 3 is a summary of the data used for both construction andvalidation of the autism diagnostic classifier. Full sets of answers tothe Autism Diagnostic Instrument-Revised questionnaire were downloadedfrom the Autism Genetic Research Exchange (AGRE), the Simons Foundation(Simons), and the Boston Autism Consortium (AC). The AGRE data were usedfor training, testing, and construction of the classifier. The Simonsand AC data were used for independent validation of the resultingclassifier. Table 3 lists the total numbers of autistic and non-autisticindividuals represented in each of the three data sets with a breakdownof age by quartiles.

TABLE 3 Classifier Data Validation Data AGRE Simons AC Autism Not MetAutism Not Met Autism Not Met Sample Size 891 75 1,654 4 308 2 Q1 (Age)6.44 6.38 6.75 8.38 6.50 5.42 Median (Age) 8.06 9.24 8.75 9.75 8.50 9.50Q3 (Age) 10.84 11.88 11.25 12.25 11.54 13.58 IQR (Age) 4.4 5.5 4.5 3.885.04 8.17

The classifier performed with high accuracy on both the Simons and ACdata sets. All individuals in the SSC previously diagnosed with autismwere accurately classified as autistic by the classifier. In the AC, theclassifier accurately classified 321 of the 322 autistic cases (99.7%accuracy). Interestingly, the single misclassified individual from ACwas predicted with a low-confidence ADTree score of 0.179 castingpossible doubt on the classification and suggesting the potential that afurther behavioral assessment of this individual could result in anon-spectrum diagnosis.

Given the limited number of individuals with the diagnosis of “not met,”i.e., non-autistic individuals who could serve as controls in thevalidation step, the invention can group the controls from all threestudies (AGRE, Simons, and AC) to increase the size of the controlpopulation to 84 individuals. In both the AC and SSC validationprocedures only 7 of the 84 control individuals were misclassified, anoverall accuracy of 92%. Further inspection of these 7 misclassifiedcontrols suggested that they likely had autism spectrum conditions andthat their ADI-R diagnoses may not be accurate. Five had a previousdiagnosis prior to recruitment to the study (2 with Asperger's Syndromeand 3 with Pervasive Developmental Disorder—Not Otherwise Specified(PDD-NOS)) and all 7 were diagnosed with either “autism” or “autismspectrum” by an alternative behavioral instrument, the Autism DiagnosticObservation Schedule (ADOS), in direct conflict with the classificationdiagnosis provided by the ADI-R. Such conflict in results furthersupported the possibility the 7 individuals misclassified by theclassifier can in fact meet the criteria necessary for a formal autismdiagnosis.

In an attempt to account for the small number of controls across allthree datasets, the invention can simulate control data (e.g., a 1,000simulated controls were generated) by random sampling from the pool ofobserved answers given by 84 control individuals classified as notmeeting some or all criteria for autism diagnosis. The classifierperformed with 99.9% accuracy on these 1,000 simulated controls,misclassifying only one.

Given the importance of diagnosis at early ages, the invention can alsotest the accuracy of the classifier on the collection of answers fromchildren diagnosed at ages below 5. Although 5 of the 7 questions in theclassifier probe for the most abnormal behavior between 4 and 5 years ofage, according to the invention, the answers to those questions with the“current” behavior can be made equally accurate and allow expansion toyounger children. Only the AGRE and AC datasets contained sufficientnumbers of children below age 5 and thus the present invention need notuse the SSC, as the Simons study restricts case recruitment to ages 4and older, to test this hypothesis. For this analysis, the invention wastested against a total of 1,589 individuals previously listed asautistic in either AGRE or AC and 88 individuals flagged as not meetingthe criteria for autism diagnosis. All but 1 of the children with autismwere correctly categorized as having autism by the classifier, a nearperfect accuracy of 99.9%, and 12 of the 88 controls were misclassifiedas having autism, corresponding to an 86% accuracy. As in the validationsteps above, all 12 of these individuals had a conflicting ADOScategorization, suggesting the possibility that additional inspectionand behavioral analysis can reveal that these 12 individuals meet thecriteria necessary for an autism diagnosis.

Discussion

Current practices for the behavioral diagnosis of autism are highlyeffective but also prohibitively time consuming. A gold standard in thefield is the Autism Diagnostic Interview-Revised (ADI-R), a 153-itemexam that yields high inter-interviewer reliability and accuracy. Theinvention can use machine learning techniques to test whether theaccuracy of the full ADI-R could be achieved with a significantlyshorter version of the exam. The analysis found a small subset of 7ADI-R questions targeting social, communication, and behavioralabilities to be 99.97% as effective as the full ADI-R algorithm fordiagnosis of 2,867 autistic cases drawn from three separaterepositories. This represents 96% fewer questions than the full ADI-Rexam and 84% fewer questions than is contained in the ADI-R algorithmitself.

The analysis used machine learning techniques to analyze previouscollections of data from autistic individuals, a practice that to datehas not been commonplace in the field, but one that promotes novel andobjective interpretation of autism data and promotes the development ofan improved understanding of the autism phenotype. In the present case,several alternative machine learning strategies of the present inventionyielded classifiers with very high accuracy and low rates of falsepositives. The top performing ADTree algorithm proved most valuable forclassification as well as for measuring classification confidence, witha nearly 100% accuracy in the diagnosis of autistic cases. The ADTreealgorithm resulted in a simple decision tree (FIG. 2) that can,according to the present invention, be readily converted into abehavioral algorithm for deployment in screening and/or diagnosticsettings. In addition, the ADTree score provided an empirical measure ofconfidence in the classification that can be used to flag borderlinecases likely warranting closer inspection and further behavioralassessment. In the present case, a small number of controls weremisclassified, but with a low confidence score that suggested furtherscreening and additional diagnostic tests might provide evidence thatthe original diagnosis was incorrect.

Limitations

The study was limited by the content of existing repositories, and as aconsequence, the invention can have a relatively small number of matchedcontrols for construction and validation of the classifier. In aprospective design for a study according to the invention, one wouldnormally include equal numbers of cases and controls for optimalcalculations of sensitivity and specificity of the classifier.Nevertheless, the clear demarcation between cases and controls foundwith the existing data (FIG. 3) provided confidence that the classifierscales to a larger population with equal or similar accuracy. Inaddition, the classifier performed with near perfect accuracy on asimulated set of 1,000 controls. While the simulated data were boundedby the empirical distribution of answers provided by the true controlindividuals, that empirical distribution covered a large space ofanswers likely to be provided by prospectively recruited controls. Theinvention can be expanded so as to include additional validation throughthe inclusion of new ADI-R data from both autistics and non-autistics.

The data used also contained a preponderance of older children, withhighest density between ages of 5 and 17, potentially making theresulting classifier biased against effective diagnosis of youngerchildren. However, the invention demonstrates near perfectclassification accuracy for children 4 years of age and younger, withthe youngest individual being 13 months (FIG. 3). As the sample sizes ofyounger children was relatively small, a larger sample can providegreater resolution and a larger set of training data to develop and testif a new classifier has greater accuracy than the one generated here.

Finally, since the classifier was trained only on individuals with orwithout classic autism it was not trained to pinpoint other diagnosesalong the autism spectrum including Asperger and Pervasive DevelopmentalDisorder—Not Otherwise Specified (PDD-NOS). This was a byproduct of thedata available at the time of study; the data used in the study did nothave sufficient granularity to test whether the classifier could beutilized for more fine-grained diagnoses. Either a large sample of ADI-Rdata from a range of ASDs or a prospective study, e.g., web-basedsurvey/questionnaire (for example, like the web-basedsurvey/questionnaire according to the present invention hosted on theHarvard Autworks website), enables measurement of the performance of theclassifier outside of classic autism, and also enables retraining of theclassifier should the performance be suboptimal.

Conclusions

Currently, the diagnosis of autism is through behavioral exams andquestionnaires that require considerable time investment on the part ofparents and clinicians. Using the present invention, the time burden forone of the most commonly used instruments for behavioral diagnosis, theAutism Diagnostic Interview-Revised (ADI-R), was significantly reduced.Deploying machine learning algorithms according to the presentinvention, the Alternating Decision Tree (ADTree) is found to have nearperfect sensitivity and specificity in the classification of individualswith autism from controls. The ADTree classifier consisted of only 7questions, 93% fewer than the full ADI-R, and performed with greaterthan 99% accuracy when applied to independent populations of autistics,misclassifying only one out of 1,962 cases. The classifier alsoperformed with equally high accuracy on children under 4 and as young as13 months, suggesting its applicability to a younger population ofchildren with autism. Given this dramatic reduction in numbers ofquestions without appreciable loss in accuracy, the findings representan important step to making the diagnosis of autism a process of minutesrather than hours, thereby enabling families to receive vital care farearlier in their child's development than under current diagnosismodalities.

Methods

Ethics Statement

The study (number: M18096-101) has been evaluated by the Harvard MedicalSchool Institutional Review Board and identified as not involving humansubjects as defined under 45CFR46.102(f) and as meeting the conditionsregarding coded biological specimens or data. As such, (a) thespecimens/data were not collected specifically for the research throughan interaction or intervention with a living person, and (b) theinvestigators cannot “readily ascertain” the identity of the individualwho provided the specimen/data to whom any code pertains. The HarvardMedical School Institutional Review Board determined the study to beexempt.

Constructing a Classifier

For constructing a classifier, phenotype data from the Autism GeneticResource Exchange (Geschwind, et al., “The autism genetic resourceexchange: a resource for the study of autism and relatedneuropsychiatric conditions,” American journal of human genetics, 2001,69(2):463-466) (AGRE) repository of families with at least one childwith autism can be used. Specifically, the answers to the 153 questionsand sub-questions in the 2003 version of ADI-R can be used. The initialanalysis can be restricted to children with a diagnosis of “autism” fromthe categories “autism,” “broad spectrum” and “not quite autism.” Havingone of these classifications was determined by the AGRE “affectedstatus” algorithms, which used the domain scores from the ADI-R toevaluate the individuals. The “autism” classification used by AGREfollows the validated algorithm created by the authors of the ADI-R. Ifa child who took the ADI-R did not meet any of these classificationcriteria, he or she was deemed “not met,” and was used as a control forthe purposes of this study. Analyses were also restricted to childrenwith and without an autism diagnosis who were 5 years of age or olderand under the age of 17 years of age as the majority of data were fromwithin this age range, thereby providing the most uniform collection ofanswers to the ADI-R and consequently the most complete matrix of datafor machine learning. These steps resulted in 891 individuals with aclassification of “autism” and 75 with a classification of “not met”(Table 3).

A series of machine learning analyses can be conducted to construct aclassifier from the 93 ADI-R questions in order to distinguishindividuals classified as “autistic” from those deemed “not met.” Inorder to find an optimal classifier given the underlying data, theperformance of 15 machine learning algorithms (Table 1) can be compared.For each algorithm, 10-fold cross validation can be used, with 90% ofthe data for training and the other 10% for testing, to build and assessthe accuracy of the resulting classifier. Such cross-validation has beenshown to perform optimally for structured, labeled data while reducingbias in the resulting classifier (Kohavi, “A study of cross-validationand bootstrap for accuracy estimation and model selection,” In:Proceedings IJCAI-95: 1995; Montreal, Morgan Kaufmann, Los Altos,Calif.: 1137-I) and was therefore best suited to the present learningtasks. For each of the 15 classifiers, the false positive rate (FPR),true positive rate (TPR), as well as the accuracy can be measured. Thespecificity (FPR) can be plotted against sensitivity (TPR) to visualizethe performance and to identify and select the optimal classifier foruse in further analysis and validation. All machine learning steps wereconducted using the Weka toolkit (Frank, et al., “Data mining inbioinformatics using Weka,” Bioinformatics, 2004, 20(15):2479-2481).

Validating the Classifier

Although the 10-fold cross validation served as an internal validationof classifier accuracy, independent, age-matched ADI-R data from otherfamilies with autism whose data have been stored in the Simons SimplexCollection (Fischbach, et al., “The Simons Simplex Collection: aresource for identification of autism genetic risk factors,” Neuron,2010, 68(2):192-195) (SSC) and in the Boston Autism Consortiumcollection (AC) can be used to test the performance of the classifier.The SSC data consisted of 1,654 individuals classified with “autism” bythe diagnostic standards of ADI-R and 4 that were found to be“nonspectrum” according to the Collaborative Programs of Excellence inAutism (CPEA) diagnostic algorithms established by Risi et al. (Risi, etal., “Combining information from multiple sources in the diagnosis ofautism spectrum disorders,” Journal of the American Academy of Child andAdolescent Psychiatry, 2006, 45(9):1094-1103). The families in the studywere all simplex, i.e., only one child in the family with an ASDdiagnosis. The AC set contained 322 individuals classified through thestandard 2003 ADI-R as having “autism” and 5 classified as “non autism.”The objective with these independent resources was to determine if theclassifier constructed from the AGRE dataset could accuratelydistinguish between an individual classified by the full ADI-R algorithmas autistic from an individual classified as not meeting the criteriafor an autism diagnosis.

Exclusion of Questions

Before running the data through the machine learning algorithms,questions can be removed from consideration if they contain a majorityof exception codes indicating that the question could not be answered inthe format requested. Also, all ‘special isolated skills’ questions andoptional questions with hand-written answers can be removed.

Simulation of Controls

Because of the low numbers of controls in any of the datasets includedin the study, the numbers can be boosted through a simple simulationprocess. For the creation of a simulated control, answers from theexisting set of 84 controls can be randomly sampled, i.e., the totalnumber of individuals who did not meet the criteria for an autismdiagnosis in all three studies, SSC, AGRE, and AC. Random sampling canbe performed for each question in the ADI-R by drawing randomly from theset of recorded answers for that question, therefore ensuring thatdistribution of answers in the simulated data were bounded by theempirical distribution in the observed answers. The process can berepeated, for example, 1,000 times and this dataset of simulatedcontrols can be used for additional measurements (e.g., input to analgorithm, which can be descriptions of observed behavior in the formatthat the algorithm requires, the answers to questions about observedbehaviors in the format that the algorithm requires, observations orquestions) of the classifier's accuracy.

Part II: Use of Machine Learning to Shorten Observation-Based Screeningand Diagnosis of Autism

Abstract

The Autism Diagnostic Observation Schedule-Generic (ADOS-G) is one ofthe most widely used instruments for behavioral evaluation of autism. Itis composed of four different modules each tailored for a specific groupof individuals based on their level of language. On average, each moduletakes between 30 to 60 minutes to deliver. A series of machine learningalgorithms can be used to study the complete set of scores to the firstmodule of the ADOS-G available at the Autism Genetic Resource Exchange(AGRE) for 612 individuals given a classification of autism and 15individuals who did not meet the criteria for a classification of autismfrom AGRE and the Boston Autism Consortium (AC). The analysis indicatedthat 8 of the 29 items contained in the first module of the ADOS-G weresufficient to diagnose autism with 100% statistical accuracy. Theaccuracy of this 8-item classifier can be tested against complete setsof scores from two independent sources, a collection of 110 individualswith autism from AC and a collection of 336 individuals with autism fromthe Simons Foundation. (Other independent sources can be used includingbut not limited to National Database for Autism Research, The AutismGenetic Research Exchange or any suitable repository of data.) In bothcases, the classifier performed with nearly 100% statistical accuracycorrectly classifying all but two of the individuals from these tworesources who previously had been diagnosed with autism through theADOS-G. With incidence rates rising, the ability to recognize andclassify autism quickly and effectively requires careful design ofassessment and diagnostic tools. The research is among a small number ofattempts to retrospectively analyze large data repositories to derive ahighly accurate, but significantly abbreviated diagnostic instrument.According to the present invention, a completely new diagnostic tool iscreated, which is designed to target elements, i.e., behaviors andmorphology, that the present machine learning processes identify asvital to a diagnosis and, critically, an algorithm is created, whichintelligently, i.e., numerically and statistically, combines the targetelements to provide a disorder/non-disorder classification. Suchretrospective analyses provide valuable contributions to the diagnosisprocess and help lead to faster screening and treatment of individualswith autism.

Introduction

Although autism has a strong genetic component (Bailey, et al., “Autismas a strongly genetic disorder: evidence from a British twin study,”Psychol Med, 1995, 25(1):63-77), it is largely diagnosed throughbehavior. Diagnosing autism has been formalized with instrumentscarefully devised to measure impairments indicative of autism in threedevelopmental areas: communication and social interactions, restrictedinterests and activities, and stereotypical behaviors. One of the mostwidely used instruments is the Autism Diagnostic ObservationalSchedule-Generic (ADOS-G) (Lord, et al., “The autism diagnosticobservation schedule-generic: a standard measure of social andcommunication deficits associated with the spectrum of autism,” Journalof Autism and Developmental Disorders, 2000, 30(3): 205-223). The ADOS-Gconsists of a variety of semi-structured activities designed to measuresocial interaction, communication, play, and imaginative use ofmaterials. The exam is divided into four modules each geared towards aspecific group of individuals based on their level of language and toensure coverage for wide variety of behavioral manifestations, withmodule 1, containing 10 activities and 29 items, focused on individualswith little or no language and therefore most typical for assessment ofyounger children. The ADOS observation is run by a certifiedprofessional in a clinical environment and its duration can range from30 to 60 minutes. Following the observation period, the administratorwill then score the individual to determine their ADOS-based diagnosis,increasing the total time from observation through scoring to between 60to 90 minutes in length.

The long length of the ADOS exam as well as the need for administrationin a clinical facility by a trained professional both contribute todelays in diagnosis and an imbalance in coverage of the populationneeding attention (Wiggins, et al., “Examination of the time betweenfirst evaluation and first autism spectrum diagnosis in apopulation-based sample,” Journal of developmental and behavioralpediatrics, IDBP 2006, 27(2 Suppl): S79-87). The clinical facilities andtrained clinical professionals tend to be geographically clustered inmajor metropolitan areas and far outnumbered by the individuals in needof clinical evaluation. Families may wait as long as 13 months betweeninitial screening and diagnosis (Lord, et al., “The autism diagnosticobservation schedule-generic: a standard measure of social andcommunication deficits associated with the spectrum of autism,” Journalof Autism and Developmental Disorders, 2000, 30(3): 205-223) and evenlonger if part of a minority population or lower socioeconomic status(Bernier, et al., “Psychopathology, families, and culture: autism,”Child Adolesc Psychiatr Clin N Am, 2010, 19(4):855-867). These delaysdirectly translate into delays in the delivery of speech and behavioraltherapies that have significant positive impacts on a child'sdevelopment, especially when delivered early (Howlin, “Children withAutism and Asperger's Syndrome: A Guide for Practitioners and Parents,”Chichester, UK: Wiley; 1998) (Pisula, “Parents of children with autism:review of current research,” Arch Psychiatry Psychother, 2003, 5:51-63).Thus a large percentage of the population is diagnosed afterdevelopmental windows when behavioral therapy would have had maximalimpact on future development and quality of life. The average age ofdiagnosis in the United States is 5.7 years and an estimated 27% remainundiagnosed at 8 years of age. At these late stages in development, manyof the opportunities to intervene with therapy have evaporated.

Attention has been paid to the design of abbreviated screeningexaminations that are meant to foster more rapid diagnosis, includingthe Autism Screening Questionnaire (ASQ, designed to discriminatebetween PDD and non-PDD diagnoses (Berument, et al., “Autism screeningquestionnaire: diagnostic validity,” Br J Psychiatry, 1999,175:444-451)), the Modified Checklist for Autism in Toddlers (MCHAT)(Robins, et al., “The Modified Checklist for Autism in Toddlers: aninitial study investigating the early detection of autism and pervasivedevelopmental disorders,” J Autism Dev Disord, 2001, 31(2):131-144), andthe Parents' Evaluation of Developmental Status (PEDS) (Pinto-Martin, etal., “Screening strategies for autism spectrum disorders in pediatricprimary care,” J Dev Behav Pediatr, 2008, 29(5):345-350), to name a few.However, the ADOS, due to its high degree of clinical utility anddiagnostic validity, remains one of the dominant behavioral tools forfinalizing a clinical diagnosis. Research has focused on manualselection of preferred questions from the full ADOS for use in scoringfollowing the observation period, and while this work has led tocritical advances in diagnostic validity and steps toward a reliablemeasure of severity, no efforts have focused on selection of ADOSquestions to enable shortening of the diagnosis process overall.

The aim in the present study was to statistically identify a subset ofitems from the full ADOS module 1 that could enable faster screeningboth in and out of clinical settings, but that does not compromise thediagnostic validity of the complete ADOS. As a valuable byproduct of thewidespread adoption and use of ADOS-G, research efforts have bankedlarge collections of score sheets from ADOS together with the clinicaldiagnosis that can be utilized to address this aim directly. Leveragingthese large databases, a collection of full ADOS evaluations for over1,050 children can be collected, focusing on module 1 data alone thatprovides key insight into the development of shorter approaches forearly detection. By application of machine learning methods, classifierscan be constructed and the sensitivity and specificity of each can beobjectively measured with respect to diagnostic validity and similarityas compared to the original ADOS-G algorithms. According to the presentinvention, one classifier, a classifier based on the decision treelearning, performed optimally for classification of a wide range ofindividuals both on and off the spectrum. This classifier wassignificantly shorter than the standard ADOS and pinpointed several keyareas for behavioral assessment that could guide future methods forobservation-based screening and diagnosis in as well as out of clinicalsettings.

Methods

Constructing a Classifier

ADOS-G Module 1 data from the Autism Genetic Resource Exchange (AGRE)(Geschwind, et al., “The autism genetic resource exchange: a resourcefor the study of autism and related neuropsychiatric conditions,”American journal of human genetics, 2001, 69(2):463-466) repository offamilies with at least one child diagnosed with autism can be used asthe input for machine learning classification. The ADOS-G examinationclassifies individuals into categories of “autism” or “autism spectrum”based on the ADOS-G diagnostic algorithm. The diagnostic algorithm addsup the scores from 12 (original) to 14 (revised) items and classifiesindividuals as having autism or autism spectrum according to thresholdsscores. Those individuals who did not meet the required threshold wereclassified as “non-spectrum” and were used as controls in the study. Forthe purposes of the analysis, the analysis can be restricted to onlythose with the classification of “autism.” Any individuals who wereuntestable or where the majority of their scores were unavailable wereexcluded from the analysis. The final data matrix contained 612individuals with a classification of “autism” and 11 individuals with aclassification of “non-spectrum” (Table 4).

Table 4 sets forth a summary of the data used for both construction andvalidation of the autism diagnostic classifier. Complete sets of answersto the Autism Diagnostic Observation Schedule-Generic evaluation can beacquired from the Autism Genetic Research Exchange (AGRE), the SimonsFoundation (Simons), and the Boston Autism Consortium (AC). The tablelists the total numbers of individuals classified as having autism andindividuals classified as non-spectrum represented in each of the threedata sets as well as a breakdown of age using the interquartile range.

TABLE 4 AGRE AC Simons Non- Non- Non- Spec- Spec- Spec- Autism trumAutism trum Autism trum Sample 612 11 110 4 336 0 Size Q1 4.7375 2.993.6875 2.771 5.167 0 Median 6.64 4.57 5.625 3.083 6.75 0 Q3 8.86 6.938.4167 6.729 10 0 IQR 4.1225 3.94 4.7292 3.958 4.833 0

In the study, a classifier can be constructed by performing a series ofmachine learning analyses (performed using Weka (Hall, et al., “The WEKAData Mining Software: An Update,” SIGKDD Explorations, 2009, 11(1):1))on the 29 ADOS-G items from module 1 to differentiate betweenindividuals with a classification of “autism” from those with aclassification of “non-spectrum.” The sensitivity, specificity, andaccuracy of 16 machine learning algorithms can be compared to create thebest classifier (Table 5).

Table 5 sets forth the 16 machine learning algorithms used to analyzethe module 1 ADOS-G data used for training the classifier. Thesealgorithms were executed using the toolkit WEKA. The false positive rate(FPR) and true positive rate (TPR) are provided along with the overallaccuracy. Both the Alternating Decision Tree (ADTree) and the functionaltree (FT) performed with 100% accuracy. The ADTree can be chosen overthe FT for further analysis because the former uses eight items comparedto the nine items used in the latter.

TABLE 5 Classifier Name Description FPR TPR Accuracy ADTree An ADTreecombines decision trees, voted 0.000 1.000 1.000 decision trees, andvoted decision stumps. The algorithm is based on boosting, which yieldsaccurate predictions by combining a series of “weak” learners thattogether, can classify accurately (Freund, et al., “The alternatingdecision tree learning algorithm,” In: Machine Learning: Proceedings ofthe Sixteenth International Conference 1999, 124-133). BFTree The topnode of the decision tree splits the data so 0.600 0.993 0.979 themaximum reduction of impurity (misclassified data) is achieved. This iscalled the “best” node, and it is expanded upon first (unlike in a C4.5tree, for example, where nodes are expanded upon according todepth-first) (Shi, “Best-first Decision Tree Learning,” Master Thesis,The University of Waikato, 2007). Decision A DecisionStump classifier isa single-level 1.000 1.000 Stump decision tree with one node. Terminalnodes extend directly off of this node, so a classification is madebased on a single attribute (Freund, et al., “Experiments with a newboosting algorithm,” In: Proceedings of the International Conference onMachine Learning: 1996; San Francisco, Morgan Kautinann: 148-156). FTFunctional trees are classification trees which can 0.000 1.000 1.000use multiple linear regression or multiple logistic regression atdecision nodes and linear models at leaf nodes (Gama J: FunctionalTrees. Machine Learning 2004, 219-250). J48 J48 is a Java implementationof the C4.5 0.200 0.998 0.994 algorithm; it generates either pruned oran unpruned or C4.5 decision tree. C4.5 build trees from training datausing the concept of information entropy (Quinlan, “C4.5,” San Mateo:Morgan Kaufmann Publishers; 1993). J48graft This class generates agrafted C4.5 decision tree 0.333 1.000 0.992 that can either be prunedor unpruned. Grafting adds nodes to already created decision trees toimprove accuracy (Freund, et al., “The alternating decision treelearning algorithm,” In: Machine Learning: Proceedings of the SixteenthInternational Conference 1999, 124-133). Jrip This classifier is anoptimized version of 0.333 0.995 0.987 Incremental Reduced Error Pruningimplementing a propositional learner, RIPPER (Repeated IncrementalPruning to Produce Error Reduction) (Cohen, “Fast Effective RuleInduction,” Twelfth International Conference on Machine Learning,1995:115-123). LADTree LADTree produces a multi-class alternating 0.1330.997 0.994 decision tree. It has the capability to have more than twoclass inputs. It performs additive logistic regression using theLogitBoost strategy (Holmes, et al., “Multiclass alternating decisiontrees,” ECML, 2001:161-172). LMT Logistic model trees combine decisiontrees with 0.133 1.000 0.997 logistic regression models. LMTs aregenerated by creating a logistic model at the root using LogitBoost. Thetree is extended at child nodes by using LogitBoost. Nodes are splituntil no additional split can be found (Landwehr, et al., “LogisticModel Trees,” Machine Learning, 2005, 161-205). Nnge Nearest neighboralgorithms define a distance 0.200 0.998 0.994 function to separateclasses. By using generalized exemplars it reduces the role of thedistance function (relying too heavily on the distance function canproduce inaccurate results) by grouping classes together (Martin,“Instance-Based learning : Nearest Neighbor With Generalization,”Hamilton, New Zealand.: University of Waikato; 1995). OneR Thisalgorithm finds association rules. It finds the 0.400 0.993 0.984 oneattribute that classifies instances so as to reduce prediction errors(Holte, “Very simple classification rules perform well on most commonlyused datasets,” Machine Learning: Proceedings of the SixteenthInternational Conference, 1993, 11:63-91). PART A set of rules isgenerated using the “divide- 0.200 1.000 0.995 and-conquer” strategy.From here, all instances in the training data that are covered by thisrule get removed and this process is repeated until no instances remain(Frank, et al., “Generating Accurate Rule Sets Without GlobalOptimization,” In: Machine Learning: Proceedings of the FifteenthInternational Conference: 1998; San Francisco, CA, Morgan KaufmannPublishers). RandomTree The RandomTree classifier draws trees at 0.4000.987 0.978 random from a set of possible trees with k random featuresat each node and performs no pruning (Breiman, “Random Forest,” MachineLearning, 2001, 45: 5-32). REPTree An REPTree is a fast decision treelearner that 0.467 0.998 0.987 constructs a decision/regression treeusing information gain for splitting, and prunes the tree usingreduced-error pruning with backfitting (Witten, et al., “Data Mining:Practical Machine Learning Tools and Techniques with JavaImplementations,” Morgan Kaufmann, Amsterdam [etc.], second edition,October 2005). Ridor This classifier is an implementation of a Ripple-0.267 0.997 0.990 Down Rule Learner. An example of this is when theclassifier picks a default rule (based on the least weighted error), andcreates exception cases stemming from this one (Gaines, et al.,“Induction of Ripple-Down Rules Applied to Modeling Large Databases,” JIntell Inf Syst, 1995, 5(3):211-228). Simple Cart Classification andregression trees are used to 0.667 0.992 0.976 construct predictionmodels for data. They are made by partitioning the data and fittingmodels to each partition (Breiman, et al., “Classification andRegression Trees,” Wadsworth International Group, Belmont, California,1984).

For each algorithm, 10-fold cross-validation can be used, utilizing 90%for training and the remaining 10% for testing to construct and measurethe accuracy of the resulting classifier. This procedure has beenpreviously shown to perform optimally for structured, labeled data whilereducing bias in the resulting classifier (Kohavi, “A study ofcross-validation and bootstrap for accuracy estimation and modelselection,” In: Proceedings IJCAI-95: 1995; Montreal, Morgan Kaufmann,Los Altos, Calif.: 11374). The specificity of the classifiers can beplotted against its sensitivity to visualize the performance as well asto determine the most accurate classifier for each module.

Validating the Classifier

Beyond the 10-fold cross-validation, the classifier can be validated bytesting it on independently collected ADOS-G data from other individualswith autism in the Boston Autism Consortium (AC) and the Simons SimplexCollection (Fischbach, et al., “The Simons Simplex Collection: aresource for identification of autism genetic risk factors,” Neuron,2010, 68(2):192-195) (SSC). The AC data included 110 individualsclassified by the ADOS-G module 1 algorithm as “autistic” and anadditional four individuals who were considered “non-spectrum.” The SSCdata comprised 336 individuals classified as “autistic” and noindividuals who were found to be off the spectrum following the ADOSexam.

Balancing Classes Through Simulation

Because machine learning algorithms maximize performance criteria thatplace equal weight on each data point without regard to classdistinctions, controls can be simulated to increase the number of scoresheets that correspond to an ADOS-G classification of “non spectrum.”This enabled a test as to whether the imbalance in the classes of autismand non-spectrum inadvertently introduced biases that skew downstreamresults and interpretation. To create a simulated control, scores can berandomly sampled from the existing set of 15 controls, i.e., the totalnumber of individuals who did not meet the criteria for a classificationof “autism” in all three studies. The simulated control can be done foreach of the 29 items in the ADOS-G module 1 by randomly drawing from theset of recorded scores for that item. This guaranteed that the simulatedscores were drawn from the same distribution of observed scores. Thisprocess was repeated 1,000 times to create artificial controls that weresubsequently used to further challenge the specificity of theclassifier, i.e., its ability to correctly categorize individuals withatypical development or apparent risk of neurodevelopmental delay butnot on the autism spectrum. The simulated controls can be utilized torecreate a classifier based on data with balanced classes, 612 observedADOS-G score sheets for individuals categorized as having autism and 612individuals (15 observed+597 simulated) not meeting ADOS-G criteria foran autism diagnosis.

Results

The classifier can be constructed for module 1 using ADOS-G data fromthe Autism Genetic Resource Exchange (AGRE). Because the AGRE datacontained only 11 controls for module 1, all other module 1 individualscan be included with a classification of “non-spectrum” from the BostonAutism Consortium (AC) in the analysis bringing the total number ofcontrols up to 15. The accuracy of the classifier can be improved whencompared to the accuracy of only using the 11 controls from AGRE. Theperformance of 16 different machine learning algorithms on the 29 itemsin module 1 (Table 5) can be tested. The best algorithm can be selectedby comparing the sensitivity, specificity, and accuracy (FIG. 4).

FIG. 4 shows receiver operator curves mapping sensitivity versusspecificity for the 16 different machine learning algorithms tested onthe module 1 Autism Diagnostic Observational Schedule-Generic (ADOS-G)training data. The best classifiers can be identified as those closestto the point (1, 0) on the graph indicating perfect sensitivity (truepositive rate) and 1-specificity (false positive rate). The bestperforming model was the alternating decision tree (ADTree) andfunctional tree (FT). The ADTree was chosen over the FT because it usedfewer items. See Table 5 for a summary of the 16 machine learningalgorithms used in the analysis.

For module 1, two algorithms, the alternating decision tree (Freund, etal., “The alternating decision tree learning algorithm,” In: MachineLearning: Proceedings of the Sixteenth International Conference 1999,124-133) and the functional tree (Gama J: Functional Trees. MachineLearning 2004, 219-250), operated with perfect sensitivity, specificity,and accuracy. However, the alternating decision tree used eightquestions while the functional tree used nine. Because it is the goal toshorten the exam without appreciable loss of accuracy, the alternatingdecision tree (ADTree) can be selected as the optimum algorithm forfurther analysis and validation. The ADTree classifier correctlyclassifies all 612 individuals from AGRE who previously received adesignation of “autism” by the ADOS-G module 1 algorithm as well as all15 individuals from AGRE and AC who were given a classification of“non-spectrum” by the ADOS-G module 1 algorithm. The ADTree classifierconsisted of only eight items out of the 29 used in the analysis. Thoseeight items included A2, B1, B2, B5, B9, B10, C1, and C2 (Table 6).

Table 6 shows the eight items used in the ADTree model. Listed are thequestion code used by Autism Genetic Research Exchange (AGRE), a briefdescription of the question, and the domain to which the questionbelongs.

TABLE 6 Question Code Question subject Core Domain A2 Frequency ofVocalization Communication Directed to Others B1 Unusual Eye ContactSocial Interaction B2 Responsive Social Smile Social Interaction B5Shared Enjoyment in Interaction Social Interaction B9 Showing SocialInteraction B10 Spontaneous Initiation of Joint Social InteractionAttention C1 Functional Play with Objects Play C2 Imagination/CreativityPlay

These eight items segregated into two of three main functional domainsassociated with autism, language/communication and social interactions,both important indicators of autism. Item A2 (vocalization directed toothers) corresponded to the language and communication domain. Items B1(unusual eye contact), B2 (responsive social smile), B5 (sharedenjoyment in interaction), B9 (showing), and B10 (spontaneous initiationof joint attention) all correspond to the domain of social interaction.Items C1 (Functional Play) and C2 (Imagination/Creativity) were designedto assess how a child plays with objects. The eight items form theelements of a decision tree that enabled classification of either“autism” or “non-spectrum” (FIG. 5).

FIG. 5 is a decision tree and official behavioral classifier generatedby the Alternating Decision Tree (ADTree) algorithm of the presentinvention. The ADTree was found to perform best out of 16 differentmachine learning approaches (FIG. 4, Table 5). The resulting treeenables one to follow each path originating from the top node, sum theprediction values and then use the sign to determine the class. In thiscase, a negative sum yielded the classification of autism while apositive sum yielded the classification of non-spectrum. Additionally,the magnitude of the sum is an indicator of prediction confidence.

Two items appeared more than once in the tree (B9 and B10), whichsupported the possibility that these items play a relatively moreimportant role in arriving at a classification of autism and that thedomain of social interaction can have more utility in theobservational-based screening and diagnosis of autism. Each item in thetree either increased or decreased a running total score known as theADTree score. A negative score indicated a classification of “autism”while a positive score yielded the classification “not-spectrum.”Importantly, the amplitude of the score provided a measure of confidencein the classification outcome, with larger absolute values indicatinghigher confidence overall, as previously indicated in Freund (Freund, etal., “A decision-theoretic generalization of on-line learning and anapplication to boosting,” Journal of Computer and System Sciences, 1997,55, 119-139). In the study, the vast majority of the scores were awayfrom the borderline for both the case and control classes (FIG. 6)indicating that the predictions made by the classifier were by-and-largerobust and unambiguous.

FIG. 6 is a graph showing the Alternating Decision Tree (ADTree) scoresof individuals in the Autism Genetic Resource Exchange, Boston AutismConsortium, and Simons Simplex Collection data sets versus their age inyears. A majority of the ADTree scores are clustered towards greatermagnitudes according to their respective classifications, regardless ofage.

For independent validation of the 8-question classifier, score sheetscan be collected for module 1 from the Boston Autism Consortium (AC) andSimons Simplex Collection (SSC). Here the objective was to determine inthe classifier could correctly recapitulate the diagnosis, autism vs.not, provided by the ADOS-G assessments of the individuals recruited tothese two independent studies. The classifier correctly classified all110 individuals previously diagnosed with “autism” in AC as well as allfour controls as “non-spectrum.” The classifier also performed with highaccuracy on the SSC dataset misclassifying only two of 336 individualsgiven a classification of “autism” in the original SSC (99.7% accuracy).Upon further examination of the two misclassified individuals from SSC,their ADTree scores were near zero, at 0.1 and 0.039. Theselow-confidence scores strongly suggested that the classifications shouldbe questioned and that additional, more rigorous assessment of these twoindividuals would likely lead to a reversal of their diagnosis.

Due to the limited number of controls in module 1, 1,000 controls can besimulated by randomly sampling from the group of observed answers in the15 individuals classified as “non-spectrum.” This procedure enablesconstruction of a series of artificial score sheets for the ADOS-Gmodule 1 that were within the bounds of answers likely to be provided byprospectively recruited individuals who would not receive a diagnosis ofautism following an ADOS-G exam. The classifier correctly classified 944out of the 1,000 simulated controls (94.4% accuracy). Upon lookingcloser at the 56 simulated individuals who were given an incorrectclassification of “autism” instead of “non-spectrum,” all but six ofthem had ADTree scores less than one point away from receiving aclassification of “non-spectrum.” Had these been real individuals,further screening and additional diagnostic tests can be suggested todetermine if the ADTree classification was correct or not.

Because of the small number of controls and imbalance in the numbers ofcases and controls, a machine learning procedure called upsampling canbe performed to assess and rule out biases in the original classifier.Upsampling effectively balances the numbers of cases and controls byprogressive sampling from the population of observed data. A classifiercan be constructed using the ADTree algorithm with the 612 individualswith a classification of “autism” from AGRE and 612 individuals with aclassification of “non-spectrum” of which 11 were from AGRE, four werefrom AC, and the remaining 597 were from the simulated controls. Theresulting classifier correctly classified 609 out of the 612 individualswith autism and all 612 individuals with a classification of“non-spectrum” (99.8% accuracy). The resulting ADTree consisted of sevenitems, six of which were also in the original classifier derived fromimbalanced data. Additionally, the ensuing alternating decision treeclosely resembled that of the original (FIG. 7), lending further supportfor the robustness of the classifier and supporting the notion that theimbalance of classes did not introduce appreciable bias in the results.

FIG. 7 is a decision tree and classifier generated by the AlternatingDecision Tree (ADTree) algorithm when applied to upsampling thecontrols. The resulting tree closely resembles that of the original tree(FIG. 5). The general shape of the tree remains the same, e.g., the leftbranch is nearly identical to the original.

Current practices for the behavioral diagnosis of autism can beeffective but in many cases overly prohibitive and time consuming. Oneof the most widely used instruments in the field of autism spectrumdisorders is the Autism Diagnostic Observational Schedule-Generic(ADOS-G), an exam broken up into four modules to accommodate a widevariety of individuals. Machine learning techniques can be used todetermine if the classification accuracy of the full ADOS-G could beachieved with a shorter version of the exam. The analysis found a smallsubset of eight ADOS-G questions from module 1 targeting social,communication, and language abilities to be 99.8% as effective as thefull ADOS-G module 1 algorithm for classifying 1,058 individuals withautism and 15 individuals classified as “non-spectrum” drawn from threeindependent repositories. This eight-item classifier represents a 72.4%reduction of the full module 1 ADOS-G exam.

The objective reduction in the number of items from the module 1 versionof ADOS-G also enabled a logical reduction in the activities associatedwith the exam. Module 1 contains ten activities (Table 7) each designedto elicit specific behaviors and responses that are coded in the 29items. With the reduction of the number of items from 29 to 8, 2 of the10 activities, namely “response to name” and “response to jointattention” could be immediately eliminated as neither are required forthe 8-question classifier (Table 7).

Table 7 shows the ten activities used in the original module 1 ADOS-Gexamination. Listed are the name of the activity and whether or not theactivity still remains relevant after removing 21 of the 29 items fromthe original ADOS-G module 1.

TABLE 7 Activity Keep? Free Play Yes Response to Name No Response toJoint Attention No Bubble Play Yes Anticipation of a Routine withObjects Yes Responsive Social Smile Yes Anticipation of a Social RoutineYes Functional and Symbolic Imitation Yes Birthday Party Yes Snack Yes

If one makes the rough assumption that each activity requires the sameamount of time to administer, then this reduction of activities wouldcorrespond to minimum time reduction of 20%. This means that the examwill take on average 24 to 48 minutes instead of 30 to 60 minutes.However, because there are fewer items to score, it is feasible that thechild will exhibit all behaviors required to score the eight items wellbefore carrying out all eight activities. Under such circumstances, theexam would conceivably take significantly less time that the 20%reduction predicted from the above assumptions.

The analysis used machine learning techniques to analyze previouscollections of data from individuals with autism, a practice thatcurrently has not been commonplace in the field, but one that promotesnovel and objective interpretation of autism data and promotes thedevelopment of an improved understanding of the autism phenotype. In thepresent case, several alternative machine learning strategies of thepresent invention yielded classifiers with very high accuracy and lowrates of false positives. The top performing ADTree algorithm provedmost valuable for classification as well as for measuring classificationconfidence, with a nearly 100% accuracy in the diagnosis of individualswith autism across three repositories. The ADTree algorithm resulted ina simple decision tree (FIG. 5) that can, according to the presentinvention, be easily converted into a behavioral algorithm for use inboth screening and/or diagnostic settings. Additionally, it can,according to the present invention, be used to inform mobile healthapproaches, for example, through a web-based video screening tools (forexample, like the web-based video screening tools according to thepresent invention hosted on the Harvard Autworks website). In addition,the ADTree score provided an empirical measure of confidence in theclassification that can flag borderline individuals likely warrantingcloser inspection and further behavioral assessment. In the presentcase, a small number of controls were misclassified, but theirlow-confidence scores suggested further screening and additionaldiagnostic tests would result in a correct diagnosis.

An exam that preserves the reliability of the ADOS-G but can beadministered in less time enables more rapid diagnosis, higherthroughput, as well as timely and more impactful delivery of therapy.

Limitations

The study was limited by the content of existing repositories, that, forreasons related to the recruitment processes of those studies, containvery few individuals who did not meet the criteria for an autismdiagnosis based on ADOS-G. In a prospective design for a study accordingto the invention, one would normally include equal numbers of cases andcontrols for optimal calculations of sensitivity and specificity of theclassifier. The validation can be expanded through the inclusion of newADOS-G data from both individuals with autism and individuals withoutautism.

Again because of limitations in available data, the classifier wastrained only on individuals with or without classic autism. Withsufficient data, the present invention may be adapted to test whetherthe classifier could accurately distinguish between autism, Asperger'ssyndrome, and Pervasive Developmental Disorder-Not Otherwise Specified(PDD-NOS). Those individuals not meeting the formal criteria for autismdiagnosis were generally recruited to the study as high-risk individualsor as siblings of an individual with autism. Thus, these controls mayhave milder neurodevelopmental abnormalities that correspond to othercategories outside of classic autism. Given that the classifiergenerally performed well at distinguishing these individuals from thosewith classic autism supports the possibility that the classifier alreadyhas inherent sensitivity to behavioral variants within, and outside, ofthe autism spectrum. Additional ADOS-G data from a range of individualswith autism spectrum disorders enables measurement of the value beyondthat of classic autism as well as enables retraining of the classifierif the accuracy is low.

Conclusions

Currently, autism is diagnosed through behavioral exams andquestionnaires that require significant time investment for both parentsand clinicians. In the study, the amount of time required to take one ofthe most widely used instruments for behavioral diagnosis, the autismdiagnostic observation schedule-generic (ADOS-G), can be reduced. Usingmachine learning algorithms according to the present invention, thealternating decision tree performs with almost perfect sensitivity,specificity, and accuracy in distinguishing individuals with autism fromindividuals without autism. The alternating decision tree classifierconsisted of eight questions, 72.4% fewer than the full ADOS-G, andperformed with greater than 99% accuracy when applied to independentpopulations of individuals with autism misclassifying only two out of446 cases. Given this dramatic reduction in the number of items withouta considerable loss in accuracy, the findings represent an importantstep forward in making the diagnosis of autism a process of minutesrather than hours, thereby allowing families to receive vital care farearlier in their child's development than under current diagnosticmodalities.

Part III: Diagnosis of Autism with Reduced Testing

The present disclosure provides, in some embodiments, methods fordiagnosing autism, such as but not limited to, autism spectrum disorder.In some embodiments, the methods are carried out by a computer, whichincludes all electronic devices having a processor capable of executingprogram instructions. Computer-readable medium containing instructionsto carry out the methods are also disclosed, along with computationalapparatuses for carrying out the methods. Accordingly, all featuresdisclosed for the provided methods are also applicable to the media andcomputational apparatuses.

Thus, one embodiment of the present disclosure provides a method fordiagnosing autism, comprising determining whether a subject suffers fromautism with a multivariate mathematical algorithm taking a plurality ofmeasurements (e.g., input to an algorithm, which can be descriptions ofobserved behavior in the format that the algorithm requires, the answersto questions about observed behaviors in the format that the algorithmrequires, observations or questions) as input, wherein the plurality:

-   -   (a) comprises no more than 25, or alternatively 20, 19, 18, 17,        16, 15, 14, 13, 12, 11, 10, 9 or 8 measurement items selected        from the Autism Diagnostic Observation Schedule-Generic (ADOS-G)        first module,    -   (b) does not include measurement items based on the “response to        name” activity of the ADOS-G first module, or    -   (c) does not include measurement items based on the “response to        joint attention” activity of the ADOS-G first module, and    -   (d) wherein the determination is performed by a computer        suitably programmed therefor.

In one aspect, the method further comprises taking the plurality ofmeasurements from the subject. In another aspect, the measurements aretaken on a video clip. In some embodiments, therefore, the video clipincludes observation of a patient in a non-clinical environment, such ashome. In some embodiments, the patient being video recorded is asked anumber of questions that are determined to be suitable for diagnosingautism in the patient by the present disclosure. In one aspect, thevideo clip is shorter than about 10 minutes. In another aspect, thevideo clip is between about 2 and 5 minutes long. In certainembodiments, the video clips are recorded and/or displayed on a mobiledevice, or displayed using a web interface.

In one aspect, the plurality comprises no more than 8 measurement itemsselected from the ADOS-G first module. In another aspect, the pluralitycomprises at least 5 measurement items selected from the ADOS-G firstmodule.

In one aspect, the plurality does not include measurement items based onthe “response to name” activity or the “response to joint attention”activity of the ADOS-G first module.

In one aspect, the plurality comprises at least 5 types of activities ofthe ADOS-G first module. In another aspect, the plurality consistsessentially of measurements items selected from the ADOS-G first module.

In some embodiments, the multivariate mathematical algorithm comprisesalternating decision tree (ADTree), or any machine learning methods orstatistical methods suitable for the diagnosis, which can be ascertainedwith methods known in the art.

In one aspect, the determination achieves a greater than about 95%prediction accuracy. In another aspect, the determination achieves agreater than 95% specificity and a greater than 95% sensitivity.

In a particular aspect, the measurement items selected from the ADOS-Gfirst module consist of:

Frequency of Vocalization Directed to Others (A2);

Unusual Eye Contact (B1);

Responsive Social Smile (B2);

Shared Enjoyment in Interaction (B5); Showing (B9);

Spontaneous Initiation of Joint Attention (B10);

Functional Play with Objects (C1); and Imagination/Creativity (C2).

Also provided is a non-transitory computer-readable medium comprisingprogram code for diagnosing autism, which program code, when executed,determines whether a subject suffers from autism with a multivariatemathematical algorithm taking a plurality of measurements as input,wherein the plurality:

-   -   (a) comprises no more than 15 measurement items selected from        the Autism Diagnostic Observation Schedule-Generic (ADOS-G)        first module,    -   (b) does not include measurement items based on the “response to        name” activity of the ADOS-G first module, or    -   (c) does not include measurement items based on the “response to        joint attention” activity of the ADOS-G first module.

Still further provided is a custom computing apparatus for diagnosingautism, comprising:

a processor;

a memory coupled to the processor;

a storage medium in communication with the memory and the processor, thestorage medium containing a set of processor executable instructionsthat, when executed by the processor configure the custom computingapparatus to determine whether a subject suffers from autism with amultivariate mathematical algorithm taking a plurality of measurementsas input, wherein the plurality:

-   -   (a) comprises no more than 15 measurement items selected from        the Autism Diagnostic Observation Schedule-Generic (ADOS-G)        first module,    -   (b) does not include measurement items based on the “response to        name” activity of the ADOS-G first module, or    -   (c) does not include measurement items based on the “response to        joint attention” activity of the ADOS-G first module.

As provided, all features disclosed for the provided methods are alsoapplicable to the media and computational apparatuses.

Another embodiment of the present disclosure provides a method fordiagnosing autism, comprising determining whether a subject suffers fromautism with a multivariate mathematical algorithm taking a plurality ofmeasurements as input, wherein the plurality comprises no more than 50,or alternatively 40, 30, 20, 15, 14, 13, 12, 11, 10, 9, 8 or 7measurement items or questions selected from the Autism DiagnosticInterview-Revised (ADI-R) exam, and wherein the determination isperformed by a computer suitably programmed therefor.

In one aspect, the method further comprises taking the plurality ofmeasurements from the subject. In another aspect, the measurements aretaken on a video clip. In some embodiments, therefore, the video clipincludes observation of a patient in a non-clinical environment, such ashome. In some embodiments, the patient being video recorded is asked anumber of questions that are determined to be suitable for diagnosingautism in the patient by the present disclosure. In one aspect, thevideo clip is shorter than about 10 minutes. In another aspect, thevideo clip is between about 2 and 5 minutes long. In certainembodiments, the video clips is recorded and/or displayed on a mobiledevice, or displayed on a web interface.

In one aspect, the plurality comprises no more than 7 measurement itemsor questions selected from the ADI-R exam. In another aspect, theplurality comprises at least 5 measurement items or questions selectedfrom the ADI-R exam. In yet another aspect, the plurality consistsessentially of measurements items or questions selected from the ADI-Rexam.

In some embodiments, the multivariate mathematical algorithm comprisesalternating decision tree (ADTree), or any machine learning methods orstatistical methods suitable for the diagnosis, which can be ascertainedwith methods known in the art.

In one aspect, the determination achieves a greater than about 95%prediction accuracy. In another aspect, the determination achieves agreater than 95% specificity and a greater than 95% sensitivity.

In a particular aspect, the measurement items or questions selected fromthe ADI-R exam consist of:

Comprehension of simple language: answer most abnormal between 4 and 5(comps15);

Reciprocal conversation (within subject's level of language): answer ifever (when verbal) (conver5);

Imaginative play: answer most abnormal between 4 and 5 (play5);

Imaginative play with peers: answer most abnormal between 4 and 5(peerp15);

Direct gaze: answer most abnormal between 4 and 5 (gazes);

Group play with peers: answer most abnormal between 4 and 5 (grplay5);and

Age when abnormality first evident (ageabn).

Also provided is a non-transitory computer-readable medium comprisingprogram code for diagnosing autism, which program code, when executed,determines whether a subject suffers from autism with a multivariatemathematical algorithm taking a plurality of measurements as input,wherein the plurality comprises no more than 20 measurement items orquestions selected from the Autism Diagnostic Interview-Revised (ADI-R)exam.

Still also provided is a custom computing apparatus for diagnosingautism, comprising:

a processor;

a memory coupled to the processor;

a storage medium in communication with the memory and the processor, thestorage medium containing a set of processor executable instructionsthat, when executed by the processor configure the custom computingapparatus to determine whether a subject suffers from autism with amultivariate mathematical algorithm taking a plurality of measurementsas input, wherein the plurality comprises no more than 20 measurementitems or questions selected from the Autism Diagnostic Interview-Revised(ADI-R) exam.

As provided, all features disclosed for the provided methods are alsoapplicable to the media and computational apparatuses.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

The disclosures illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the disclosure claimed.

Thus, it should be understood that although the present disclosure hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the disclosuresembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this disclosure. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the disclosure.

The disclosure has been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the disclosure. This includes thegeneric description of the disclosure with a proviso or negativelimitation removing any subject matter from the genus, regardless ofwhether or not the excised material is specifically recited herein.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

Part IV: Shortening the Behavioral Diagnosis of Autism ThroughArtificial Intelligence and Mobile Health Technologies

Details on initial methods to shorten the behavioral diagnosis of autismare provided below. Data were collected from three primary sources:AGRE, SSC, AC (see, Table 8, below).

TABLE 8 ADI-R ADOS AGRE

Autism Not Met

Autism Not Met Total 891 75 Total 612 11 Age 4.4 5.5 Age 4.1 3.9 SSC

Autism Not Met

Autism Not Met Total 1,654 4 Total 336 0 Age 4.5 3.8 Age 4.8 N/A AC

Autism Not Met

Autism Not Met Total 308 2 Total 110 4 Age 5.04 8.17 Age 4.7 3.9

A subset of the data was used for training and testing of a classifier(applying Artificial Intelligence, FIG. 8). The resulting classifier wasfound to contain 7 total elements and to have a testing sensitivity of100% and testing specificity of 99.1% (see, Table 9). The classifier wasthen applied to the remaining data in the above table to validate thetesting results. The accuracy of this newly derived parent-directedclassifier was well over 90% in all tests.

An ML Algorithm Performance caregiver-directed classifier is shown, forexample, in FIG. 1. A caregiver-directed classifier is shown, forexample, in FIG. 2.

Table 9 shows seven questions that achieve high accuracy in ASDdetection based on these tests.

TABLE 9 Question Code Subject 29 compsl5 comprehension of simplelanguage 35 conver5 reciprocal conversation 48 play5 imaginative play 49peerpl5 imaginative play with peers 50 gaze5 direct gaze 64 grplay5group play with peers 86 ageabn age when abnormality first evident

These seven questions translate into a complexity reduction of 93% withno loss in accuracy and also reduce exam time from 2.5 hours to lessthan 5 minutes.

Next, a validation of the ADI-R, which was modified according to thepresent invention, was performed.

Table 10 shows application of the 7 question “classifier” to new data.

TABLE 10

Autism Non-Spectrum SSC 1,654/1,654 77/84  100% 92% AC 321/322 99.7%

Sensitivity Specificity

Validation and coverage for a caregiver-directed classifier is shown,for example, in FIG. 3. Seven subjects were misclassified with autism,five had previous diagnosis, all seven met criteria for autism usinganother trusted autism screener and the classifier was apparentlyvaluable over a wide range of subject ages from 13 months to 45 years.

The invention can utilize social networks to prospectively recruitfamilies with autism into the study to further validate the accuracy ofthis reduced testing tool (see FIG. 9 and FIG. 10). FIG. 9 shows anexample of a home page for a website utilizing the present invention.The website includes a prompt to start a survey. FIG. 10 shows anexample of a welcome page and consent form for the web site utilizingthe present invention.

Over 2,000 individuals participated in less than 3 months. FIG. 11 showsthe results of the trial period. Each participant completed the surveyin minutes demonstrating rapid uptake and scalability.

An example of an existing “gold standard” is the ADOS Module 1 (see FIG.13). The ADOS Module 1 is used for individuals with limited or novocabulary, and is therefore useful for younger children. The ADOSconsists of 10 activities designed to elicit behaviors associated with29 questions. The exam takes 30-60 minutes in the clinical environment.

The invention can include a video-based classifier (see FIG. 5, FIG. 29and FIG. 36). The video based classifier includes eight questions, whichis 72% shorter than ADOS. One item focuses on language andcommunication, that is, A2: Frequency of Vocalization Directed toOthers. Five items focus on social interactions, that is, B1: UnusualEye Contact, B2: Responsive Social Smile; B5: Shared Enjoyment inInteraction; B9: Showing and B10: Spontaneous Initiation of JointAttention. Two items involve how a child or subject plays with objects,that is, C1: Functional Play with Objects, and C2:Imagination/Creativity.

An example of the validation and coverage of ADI-R, which was modifiedaccording to the present invention, is shown, for example, in FIG. 6.Here, there were only two misclassifications, both of which representmarginal scores, and both were classified as non spectrum by ADI-R.

The ADI-R includes 29 questions in the following categories:

-   -   A1 Overall Level of Non-Echoed Language    -   A2 Frequency of Vocalization Directed to Others    -   A3 Intonation of Vocalizations or Verbalizations    -   A4 Immediate Echolalia    -   A5 Stereotyped/Idiosyncratic Use of Words or Phrases    -   A6 Use of Other's Body to Communicate    -   A7 Pointing    -   A8 Gestures    -   B1 Unusual Eye Contact    -   B2 Responsive Social Smile    -   B3 Facial Expressions Directed to Others    -   B4 Integration of Gaze and other behaviors during social        overtures    -   B5 Shared Enjoyment in Interaction    -   B6 Response to Name    -   B7 Requesting    -   B8 Giving    -   B9 Showing    -   B10 Spontaneous Initiation of Joint Attention    -   B11 Response to Joint Attention    -   B12 Quality of Social Overtures    -   C1 Functional Play    -   C2 Imagination/Creativity    -   D1 Unusual Sensory Interest in Play Material/Person    -   D2 Hand and Finger and Other Complex Mannerisms    -   D3 Self-Injurious Behavior    -   D4 Unusually Repetitive Interests or Stereotyped Behaviors    -   E1 Over-activity    -   E2 Tantrums, Aggression, Negative or Disruptive Behavior    -   E3 Anxiety

Module 1 Activities include the following:

-   -   Free Play    -   Response to name    -   Response to joint attention    -   Bubble play    -   Anticipation of a routine with objects    -   Responsive social smile    -   Anticipation of a social routine    -   Functional and symbolic imitation    -   Birthday party    -   Snack

The present system and method reduces the number of activities andpresents a potential for further reduction in activities withrefinement. The present system and method can be reordered to improveefficiency. The present system and method can be adapted to providesimple parameters for home videos.

For example, a screenshot from the Autworks Video Project at HarvardMedical School is shown in FIG. 14. In this example, a display isprovided with descriptive text, an example of a video, a link to “SeeOur Videos,” a link to “Share Your Video” and a link to “Learn More”about the process.

A proof of concept for the video screening tool is shown, for example,in FIG. 15. The test included 8 analysts (basic training) and 100YouTube video, which were 2-5 minutes in length and were home-style andof variable quality. The videos were scored by the analysts using aversion of ADI-R, which was modified according to the present invention,and a version of ADOS, which was modified according to the presentinvention. The results were assessed for accuracy and inter-raterreliability.

The inter-rater reliability for the 8 analysts was shown to be high (seeFIG. 16). By combining the inter-rater results, maximum performance canbe achieved as shown, for example, in FIG. 17. In the proof of concept,there were only five misclassifications, representing an accuracy of95%.

Communities can be built using social networking tools such as Facebook,as shown, for example, in FIG. 18. Also, videos can be shared andevaluated through use of a common website such as YouTube. For example,the Autworks YouTube Channel is shown in FIG. 19. Video-based clinicalassistance includes the following steps: (1) clinician adds patient toonline system; (2) caregiver of patient provides information; (3)analyst scores video; and (4) clinician receives score report and isable to provide a preliminary assessment.

A pre-portal workflow process can include the following steps: (1)caregiver calls clinic to make appointment; (2) clinician createspatient profile on online system; and (3) system sends emailnotification and instructions to caregiver.

An example of a parent and care provider portal is shown, for example,in FIG. 20. The portal can prompt the user for a home video as shown,for example, in FIG. 21. An example of the video screening workflow isshown, for example, in FIG. 22, where members of a scoring team watch avideo and code answers based on subject behavior. Each scorer receivesclinical training. Each expert has clinically administered the ADOS.Randomly sampled videos are coded by diagnostic experts. Expert ratingsare used to assess scorers. The system automatically measuresreliability of scorers and items. For example, an example of a “Watchand Score Home Videos” system is shown, for example, in FIG. 23.

An example of a Prescreening Clinician Report is shown in FIG. 24 andincludes the following data:

-   -   VID 0001    -   Submitted: 10/19/11 12:09 PM    -   Quality Score: 8.7/10.0    -   Analysts: 5    -   Confidence 97.8%    -   Wilson, Kate    -   Caregiver: Wilson, James    -   DOB: 09/02/06    -   Gender: F    -   Clinical Action: Immediate action required. Patient shows clear        symptoms of autism spectrum disorder. High risk of classic        autism.    -   VAPR Score: 8.9/10.0    -   Recommendations:        -   i. Full ADOS            -   1. High VAPR score indicates autistic symptoms are                present. It is suggested that a clinical workup is                completed.        -   ii. Applied Behavioral Analysis (ABA)            -   1. High “eye contact” and “showing” scores indicate                patient could benefit from behavioral analysis for                support and further evaluation before clinical                appointment.        -   iii. Speech Therapy            -   1. High “vocalization” score indicates patient could                benefit from speech therapy for support and further                evaluation before clinical appointment.    -   Video-Based classifier score per analyst    -   Video-Based classifier score per question    -   DISCLAIMER: The information contained herein is based on        information provided by the patient and/or others, and no        attempt has been made to ascertain its accuracy. The material        contained herein is for informational purposes only and is not        intended to provide medical advice, diagnoses, or suggestions        for treatment. We do not warrant that the information is        complete, accurate, current or reliable or that it will be        suitable for your needs. Under no circumstances, shall anyone        else involve in creating or maintaining this information be        liable for any direct, indirect, incidental, special or        consequential damages, or lost profits that result from the use        of this information.    -   Clinician: Dr. Robert Allen, M.D.

An example of a Prescreening Clinician Report is shown in FIG. 25 andincludes the following data:

-   -   VID 0002    -   Submitted: 10/18/11 2:20 PM    -   Quality Score: 8.0/10.0    -   Analysts: 5    -   Confidence 98.5%    -   Smith, Jeremy    -   Caregiver: Smith, Susan    -   DOB: 05/23/04    -   Gender: M    -   Clinical Action: Action required but not urgent. Child shows        some symptoms of autism spectrum disorder but has high level of        cognitive function. Low risk of classic autism.    -   VAPR Score: 6.1/10.0    -   Recommendations:        -   i. Clinical workup            -   1. Moderate VAPR score indicates some autistic symptoms                are present. It is suggested that a clinical workup is                conducted.        -   ii. Speech Therapy            -   1. High “vocalization” score indicates patient could                benefit from speech therapy for support and further                evaluation before clinical appointment.    -   Video Classifier score per analyst    -   Video Classifier score per question    -   DISCLAIMER: The information contained herein is based on        information provided by the patient and/or others, and no        attempt has been made to ascertain its accuracy. The material        contained herein is for informational purposes only and is not        intended to provide medical advice, diagnoses, or suggestions        for treatment. We do not warrant that the information is        complete, accurate, current or reliable or that it will be        suitable for your needs. Under no circumstances, shall anyone        else involve in creating or maintaining this information be        liable for any direct, indirect, incidental, special or        consequential damages, or lost profits that result from the use        of this information.    -   Clinician: Dr. Robert Allen, M.D.

An example of a Prescreening Caregiver Report is shown in FIG. 26 andincludes the following data:

-   -   VID 0001    -   Submitted: 10/18/11 2:20 PM    -   Smith, Jeremy    -   Caregiver: Smith, Susan    -   DOB: 5/23/04    -   Gender: M    -   Zip Code: 02421    -   VAPR Score: 6.1/10.0    -   Recommendation: Child shows some symptoms of autism spectrum        disorder and should be evaluated by a licensed professional.        Take patient to a care facility at your earliest convenience.    -   Video    -   Map    -   Facility    -   Address    -   Phone    -   Website    -   Miles    -   DISCLAIMER: The information contained herein is based on        information provided by the patient and/or others, and no        attempt has been made to ascertain it's accuracy. The material        contained herein is for informational purposes only and is not        intended to provide medical advice, diagnoses, or suggestions        for treatment. We do not warrant that the information is        complete, accurate, current or reliable or that it will be        suitable for your needs. Under no circumstances, shall anyone        else involve in creating or maintaining this information be        liable for any direct, indirect, incidental, special or        consequential damages, or lost profits that result from the use        of this information.

Part V: Supporting Data, Experimental Data and Disclosure

FIG. 27 displays an example of a parent-/caregiver-directed classifieraccording to the invention. FIG. 27 displays the direct outcome of thedecision tree learning algorithm used on data from the gold-standardinstrument entitled “Autism Diagnostic Instrument-Revised” (ADI-R). Thedecision tree learning algorithm can be applied to the answers to thecomplete set of questions found on the ADI-R (N=93) and the diagnosticoutcome, Autism Spectrum Disorder (ASD, autism) vs. Not-Met (meant toindicate both neurotypical AND individuals with developmental delays orneurological impairments that are not ASD). The application of thedecision tree learning algorithm results in a dramatic reduction in thenumber of questions required to achieve the below depicted 100%sensitive and 99% specific classifier. Each node in the decision treerepresents one of the 7 questions, where each question represents abehavior or behavioral class deemed to be (by the machine learningprocesses of the invention) highly discerning in the recognition ofASD/autism. Three of the questions appear twice in the tree (ageabn,peerp15, play5). The 7 questions and their answers are provided inExample 1.

The input to the caregiver-directed classifier is a set of answers froma parent or caregiver of a child in his or her direct care, or aboutwhom he or she is intimately familiar. The answer are numericallyencoded from 0-8, where 8 represents “not applicable” or “cannot beanswered.” These numbers are converted into a vector and used during theexecution of the classifier. The encoded answer of each question isevaluated by the algorithm at each node in the tree, and at each node ascore is either increased or decreased. The outcome of thisclassification pipeline/process is a final score ranging between −10.0and +10.0. A negative score suggests the presence of autism spectrumdisorder, and a positive score suggests that the subject does not haveall symptoms necessary for an autism diagnosis. The magnitude of thevalue indicates the severity of the behavior and also the confidence inthe classification. Higher positive scores indicate more neurotypicalbehavior and higher negative scores indicate more severe symptoms ofautism spectrum disorders.

Example 1

The 7 questions and answer choices. The answers to these 7 questionsbecome the input to the classifier described in FIG. 27. According tothe invention, these questions and the answers are preferably understoodand answerable by the parent or caregiver without input or assistance bya clinician and within the framework of a web-based or smartdevice-based user interface.

1. How well does your child understand spoken language, based on speechalone? (Not including using clues from the surrounding environment)(compsl)

Further Consideration

-   -   Can you send her/him into another room to get something like        her/his shoes or blanket?    -   What about your purse or a book?    -   Could s/he deliver a simple message?    -   Does s/he understand if you say “no” without gesturing or        raising your voice?    -   How about “yes” or “okay”?    -   How about names of favorite foods or toys or people in your        family?    -   Do you think s/he understands 10 words? 50?

Answer according to the most abnormal behavior your child has exhibited.

-   -   0: in response to a request can place an object, other than        something to be used by himself/herself (such as the child's        shoes or toy), in a new location in a different room (For        example: “Please get the keys and put them on the kitchen        table”)    -   1: in response to a request can usually get an object, other        than something for herself/himself from a different room        (“please get the keys from the kitchen table”), but usually        cannot perform a new task with the object such as put it in a        new place    -   2: understands more than 50 words, including names of friends        and family, names of action figures and dolls, names of food        items, but does not meet criteria for the previous two answers    -   3: understands fewer than 50 words, but some comprehension of        “yes” and “no” and names of a favorite objects, foods, people,        and also words within daily routines    -   4: little or no understanding of words    -   8: Not applicable

2. Can your child have a back-and-forth conversation with you? (conver)

Further Consideration

-   -   Will s/he say something when engaged in conversation?    -   Will s/he ever ask you a question or build on what you have said        so that the conversation will continue?    -   Will s/he converse normally on topics that you have introduced?        Can s/he also introduce appropriate topics?    -   1: conversation flows, with your child and another person both        contributing to an ongoing dialogue    -   2: occasional back-and-forth conversation, but limited in        flexibility or topics    -   3: little or no back-and-forth conversation; difficult to build        a conversation; your child fails to follow conversation topic;        may ask or answer questions but not as part of a dialogue    -   4: very little spontaneous speech    -   8: Not applicable

3. Does your child engage in imaginative or pretend play? (play)

“Pretend Play” Examples

-   -   Does s/he play with toy tea sets or dolls or action figures or        cars? Does s/he drink the tea/push the car/kiss the stuffed        animal?    -   Has s/he ever given the doll a drink or the action figure a ride        in the car?    -   Has s/he ever used the doll/action figure to initiate actions,        so that the doll pours and serves the tea or the action figure        walks to the car and gets in it? Does s/he ever talk to her/his        dolls or animals?    -   Does s/he ever make them talk or make noises?    -   Has s/he ever made up a sort of story or sequence?

Further Consideration:

-   -   Does this type of play vary from day to day?

Answer according to the most abnormal behavior your child has exhibited.For children 10 years old or older, answer according to how the childplayed between the ages of 4 and 5.

-   -   0: variety of pretend play, including use of toys to engage in        play activity    -   1: some pretend play, including pretending with toys, but        limited in variety or frequency    -   2: occasional pretending or highly repetitive pretend play, or        only play that has been taught by others    -   3: no pretend play    -   8: Not Applicable

4. Does your child play pretend games when with a peer? Do theyunderstand each other when playing? (peerpl)

Further Consideration

-   -   Does s/he ever take the lead in the play activity? Or does s/he        mostly follow the other person's ideas?

Answer according to the most abnormal behavior your child has exhibited.For children 10 years or older, answer according to how she playedbetween ages 4 and 5.

-   -   0: imaginative, cooperative play with other children in which        your child leads and follows another child in pretend activities    -   1: some participation in pretend play with another child, but        not truly back-and-forth, or level of pretending/imagination is        limited in variety    -   2: some play with other children, but little or no pretending    -   3: no play with other children or no pretend play even on own    -   8: Not Applicable

5. Does your child maintain normal eye contact for his or her age indifferent situations and with a variety of different people? (gaze)

Further Consideration

-   -   Does s/he sometimes watch you walk into the room?    -   Does s/he look back and forth to your face as other children        would? What about with others?

(What is the most abnormal behavior your child has exhibited?)

-   -   0: normal eye contact used to communicate across a range of        situations and people    -   1: makes normal eye contact, but briefly or inconsistently        during social interactions    -   2: uncertain/occasional direct gaze, or eye contact rarely used        during social interactions    -   3: unusual or odd use of eye contact    -   8: Not Applicable

6. Does your child play with his or her peers when in a group of atleast two others? (grplay)

Further Consideration

Is s/he different with children or others outside your immediate family?

-   -   Does s/he play cooperatively in games that need some        participation such as musical games, hide-and-seek, or ball        games?    -   Would s/he initiate such games? Or actively seek to join in?    -   Can s/he take different parts in these games (like being chased        or doing the chasing, or hiding and looking for the other        person?)

What is the most abnormal behavior your child has exhibited? Forchildren 10 or older, please answer according to how the child behavedbetween the ages of 4 and 5.

-   -   0: actively seeks and plays cooperatively in several different        groups (three or more people) in a variety of activities or        situations    -   1: some play with peers, but tends not to initiate, or tends to        be inflexible in the games played    -   2: enjoys “parallel” active play (such as jumping in turn on a        trampoline or falling down during “ring around the rosie”), but        little or no cooperative play    -   3: seeks no play that involves participation in groups of other        children, though may chase or play catch    -   8: Not Applicable

7. When were your child's behavioral abnormalities first evident?(ageabn)

Further Consideration

-   -   What was her/his play like? What toys did s/he play with? Any        pretend games?    -   How was her/his talking then?    -   What about looking after herself/himself? Feeding? Toileting?        Dressing?    -   What were her/his relationships with other children like?    -   0: development in the first 3 years of life clearly normal in        quality and within normal limits for social, language, and        physical milestones; no behavioral problems that might indicate        developmental delay    -   1: development potentially normal during first 3 years, but        uncertainty because of some differences in behavior or level of        skills in comparison to children of the same age 2: development        probably abnormal by the age of 3 years, as indicated by        developmental delay, but milder and not a significant departure        from normal development        3: development definitely abnormal in the first 3 years, but not        obvious as autism        4: development definitely abnormal in the first 3 years and        quality of behavior, social relationships, and communications        appear to match behaviors consistent with autism

Example 2

The present invention includes a python function to implement thecaregiver-directed classifier represented in FIG. 27 given answers toall (or a majority (at least 4)) of the questions listed in Example 1.An example of code of the python function is provided in Appendix 1.

FIG. 28 is a pipeline for generating a classification score using thecaregiver-directed classifier (CDC). A caregiver interacts with a system(website, smart device application, etc.) to answer the questionsaccording to the invention (Example 1), the answers to these questionsare transformed into a discrete numerical vector and delivered as inputto the CDC (FIG. 27) to generate a score that is then plotted within adistribution of scores to create a preliminary impact report that can beused in the process of diagnosis a person with (or without) AutismSpectrum Disorder.

An example of workflow for the CDC is shown in FIG. 38. The CDC can havethe following steps: a caregiver answers a questionnaire using a webenabled device; answers to the questionnaire are converted into anumerical vector; the vector is imported into an analytical system forscoring; a CDC algorithm (such as that shown, for example, in FIG. 2) isrun natively within the analytical system; and a score and disorderclassification are computed.

FIG. 5 shows an example of the video-based classifier (VBC). FIG. 5displays the direct outcome of the decision tree learning algorithm usedon data from the gold-standard instrument entitled “Autism DiagnosticObservation Schedule” (ADOS). The invention can apply the decision treelearning algorithm to the answers to the complete set of questions foundon the ADOS-G Module 1 (N=29) and the diagnostic outcome, AutismSpectrum Disorder (ASD, autism) vs. Not-Met (meant to indicate bothneurotypical AND individuals with developmental delays or neurologicalimpairments that are not ASD). The application of the decision treelearning algorithm results in a dramatic reduction in the number ofquestions to a total of 8 given the tree classification algorithmdepicted below. The answers to these 8 questions when run through thebelow depicted classifier of the present invention yield aclassification outcome (ASD or non-ASD) that is 100% sensitive and 99%specific. Each node in the decision tree represents one of the 8questions, where each question represents a behavior or behavioral classdeemed to be (by the machine learning processes of the invention) highlydiscerning in the recognition of ASD/autism. Two of the questions appeartwice in the tree (B9 and B10). The 8 questions and their answers areprovided in Example 3.

Example 3

The 8 questions and their answer choices. The answers to these 8questions become the input to the classifier described in FIG. 5.According to the invention, these questions and the answers arepreferably understood and answerable by a video analyst (trained by thetraining materials according to the invention) without input orassistance by a clinician. The questions were also designed to bereadily answered via examination of the subject in a short (2-15 minute)video and within the framework of a web-based or smart device-based userinterface. However, the questions could be answered via other means ofobservation, including direct observation of the child.

A2: Frequency of Vocalization Directed to Others

This item is coded for the amount of socially-directed vocalization

0=Directs vocalizations to caregiver or other individuals in the videoin a variety of contexts. Must include chatting or vocalizing to befriendly or to express interest, and/or to make needs known.

1=Directs vocalizations to caregiver or other individuals in the videoregularly in one context, or directs vocalizations to caregiver or otherindividuals in the video irregularly across a variety ofsituations/contexts.

2=Occasionally vocalizes to caregiver or other individuals in the videoinconsistently in a limited number of contexts. May include whining orcrying due to frustration.

3=Almost never vocalizes or vocalizations never appear to be directed tocaregiver or other individuals in the video.

8=Not Applicable

B1: Unusual Eye Contact

Coding for this item requires that clear, flexible, socially modulated,and appropriate gaze that is used for a variety of purposes bedistinguished from gaze that is limited in flexibility, appropriateness,or contexts. This can occur at any point during the video (For example,if the subject's use of eye contact varies but at one point in the videoit is clear that the individual uses appropriate gaze, score as 0).

0=Appropriate gaze with subtle changes meshed with other communication

2=Uses poorly modulated eye contact to initiate, terminate, or regulatesocial interaction.

8=Not applicable

B2: Responsive Social Smile

This item pertains to the child's facial response to a smile and/orplayful verbal interaction with the caregiver or other individuals inthe video. The child's smile must be in response to another personrather than to an action.

0=Smiles immediately in response to smiles by the caregiver or otherindividuals in the video. This must be a clear change from not smilingto a smile that is not followed by a specific request (e.g., “Give me asmile!”).

1=Delayed or partial smile, or smiles only after repeated smiles bycaregiver or other individuals in the video, or smiles only in responseto a specific request.

2=Smiles fully or partially at the caregiver or other individuals in thevideo only after being tickled or touched in some way, or in response toa repeated action with an object (e.g., wagging a Teddy Bear in theair).

3=Does not smile in response to another person.

8=Not Applicable

B5: Shared Enjoyment in Interaction

The rating applies to his/her ability to indicate pleasure at any pointthroughout the video, not just to interact or respond.

0=Shows definite and appropriate pleasure with the caregiver or otherindividuals in the video during a couple or more activities.

1=Shows some appropriate pleasure caregiver's or other individuals inthe video during more than one activity, OR shows definite pleasuredirected to the caregiver or others in the video during one interaction.

2=Shows little or no expressed pleasure in interaction with thecaregiver or others in the video. May show pleasure in his/her ownactions or with toys.

8=Not Applicable

B9 Showing

Showing is defined as purposely placing an object so that another personcan see it. For a score of 0, this must be accompanied by eye contact.

0=Spontaneously shows toys or objects at various times during the videoby holding them up or placing them in front of others and using eyecontact with or without vocalization

1=Shows toys or objects partially or inconsistently (e.g., holds them upand/or places them in front of others without coordinated eye contact,looks from an object in his/her hands to another person without clearlyorienting it toward that person).

2=Does not show objects to another person.

8=Not Applicable

B10: Joint Attention

This rating codes the child's attempts to draw another person'sattention to objects that neither of them is touching. This does notinclude such attempts if they are for the purpose of requesting.

0=Uses clearly integrated eye contact to reference an object that is outof reach by looking at the object, then at the examiner or theparent/caregiver, and then back to the object. Eye contact may becoordinated with pointing and/or vocalization. One clear example of anattempt to draw another person's attention to an object (i.e., more thanjust referencing) is sufficient for this rating.

1=Partially references an object that is clearly out of reach. Mayspontaneously look and point to the object and/or vocalize, but does notcoordinate either of these with looking at another person, OR may lookat an object and then look at or point to the examiner or theparent/caregiver, but not look back at the object.

2=No approximation of spontaneous initiation of joint attention in orderto reference an object that is out of reach.

C1: Functional Play with Objects

This item describes appropriate use of toys.

0=Spontaneously plays with a variety of toys in a conventional manner,including appropriate play with several different miniatures (e.g.,telephone, truck, dishes, materials at a Birthday Party).

1=Some spontaneous conventional play with toys.

2=Play with toys is limited to one type despite others being available,or play with a toy is imitation rather than genuine interest.

3=No play with toys or only stereotyped play.

8=Not Applicable

C2: Imagination/Creativity

This item describes flexible, creative use of objects.

0=Pretending that a doll or other toy is something else during animaginative play scenario (e.g., using a block to give a doll a drink).

1=Self initiated Pretend play with a doll (e.g., feeding, hugging, orgiving a drink) but within context and not with the creative flexibilityrepresented in the answer above.

2=Imitates pretend play following the lead of a caregiver or otherindividual(s) in the video, but does not self-initiate pretending.

3=No pretend play.

8=Not Applicable

Example 4

The invention can include a python function to implement the video-basedclassifier represented in FIG. 5 given answers to all (or at least 4) ofthe questions listed in Example 3. An example of code of the pythonfunction is provided in Appendix 2.

FIG. 29 shows an example of a pipeline for generating a classificationscore using the video-based classifier (VBC). A caregiver interacts witha system according to the invention (including but not limited to awebsite and smart device application) to upload a home video from theircomputer, digital camera, smartphone or other device. The video is thenevaluated by video analysts (usually 2 or more for inter-raterreliability and classification accuracy) to answer the questions(Example 3) needed by the classifier (FIG. 5). The answers to thesequestions are transformed into a discrete numerical vector and deliveredas input to the VBC (FIG. 5) to generate a score that is then plottedwithin a distribution of scores to create a preliminary impact reportthat can be used in the process of diagnosis a person with (or without)Autism Spectrum Disorder.

An example of workflow for the VBC is shown in FIG. 39. The CDC can havethe following steps: acquire a video; encode the video; import the videoto an analytical system, wherein the video can be imported forsimultaneous viewing and scoring; conduct analysis and scoring of thevideo, wherein a rating subject with respect to a small number ofquestions is calculated and wherein the results are converted into avector of scores; import the scores to the VBC algorithm for scoring(such as that shown, for example, in FIG. 5); and compute a score forthe classification.

FIG. 30 shows an example of a machine learning classification method forcreating Reduced Testing Procedures (RTPs) that can be embedded intomobilized frameworks for rapid testing outside of clinical sites. Theflow chart below details the process of creating RTPs using a machinelearning algorithms on behavioral data designed for the diagnosis of ahuman condition or disease, such as autism spectrum disorder and ADHD.This classification algorithm creates a mapping from class instances(for example autism spectrum disorder vs. other) to real numbers that isdefined in terms of a set of base rules that become summed to generate areal value prediction. The classification of an instance is the sign ofthe prediction. The numerical value of the prediction indicatesconfidence in the prediction with low values being less reliable.

FIG. 31 shows an example of infrastructure for data hosting and reportgeneration using the CDC and VBC. The input system 1 is a web and smartdevice (iphone, ipad, etc) framework for registration and data input.The video hosting relational database management system (RDMS) 2securely stores videos for delivery to the video analytics framework 5and to the clinical and caregiver medical impact reports 8 and 9. Thedatabase layer contains a RDMS for storing the coded answers to both thecaregiver questions (Example 1) and the observational questions (Example3). The web input system 1 automatically encodes the former and thevideo analytics framework 5 automatically encodes the latter. Theinternal software layer contains the code needed to execute the videobased classifier (VBC) 6 and the caregiver-directed classifier (CDC) 7given a vector of answers from the vectorized score sheet RDMS 3. Thediagnostic records RDMS 4 stores all VBC and CDC scores together withsubject age, medical record data, and treatment plans. These data arecollated into a clinical impact report 8 and a caregiver knowledgereport 9. The questions, encoding, and code for the CDC are given inFIG. 1, Example 1 and Example 2. The questions, encoding, and code forthe VBC are given in FIG. 5, Example 3 and Example 4.

More details on the input system (FIG. 32, FIG. 33 and FIG. 34), thevideo analytics framework (FIG. 35), the clinical impact report (FIG.24), and the caregiver knowledge report (FIG. 26) are provided below.

FIG. 32, FIG. 33 and FIG. 34 show examples of the input system (Item 1on FIG. 31).

FIG. 35 shows an example of video analysis web framework.

The above screen shot is backed by a relational database system shown inTable 11. Table 11 displays 31 tables provided in an exemplary MySQLdatabase according to the invention.

TABLE 11   auth_group auth_group_permissions auth_messageauth_permission auth_user auth_user_groups auth_user_user_permissionsclinic_analyst clinic_clinicanswer clinic_clinicianclinic_clinicquestion clinic_clinicquestionset clinic_clinicresponseclinic_clinicscore clinic_patient clinic_video django_admin_logdjango_content_type django_openid_auth_associationdjango_openid_auth_nonce django_openid_auth_useropenid django_sessiondjango_site score_answer score_question score_questionset score_responsescore_score score_userprofile south_migrationhistory upload_video

FIG. 24 shows an example of a clinical impact report. This reportcontains the scores generated by the VBC and CDC together withinter-rater reliability information on the VBC. The report contains arecommended clinical action, matched to the score. The report alsocontains a set of treatments likely to be needed by the child based onthe severity of the score.

FIG. 26 shows an example of a parent/caregiver-directed knowledgereport. This report gives information about the child's severity andmakes a connection to the nearest and most appropriate clinical serviceprovider.

Table 12 shows an example of diagnostic records RDMS containinginformation on the score from the two classifiers, age, additionalmedical record data, treatment schedule and video file locations.

TABLE 12 CDC VBC AGE EMR Treatments Videos −9.43 −8.7 2.1 Comorbidities,ABA fdms1, parental Behavioral fdms2 diseases, therapy −5.43 −4.5 3.3Fragile X, ABA Crohn's disease Behavioral in mother therapy . . . . . .. . . . . . . . . . . .

Part VI: Smart Device-Deployed Tool

The invention can include a smart device-deployed tool, designed as amachine-specific tool for rapid capture and delivery of home videossuitable for the video-based classifier. In one embodiment, a tool thatis compatible with an iPhone, iPad or iTouch includes xCode (Apple'ssoftware development environment) classes, xib and storyboard files tocreate an autism video uploader User Interface.

Examples of code for the smart device-deployed tool are provided inAppendices 3 through 13, inclusive. Specifically, Appendix 3 lists codefor “SurveyController.h,” Appendix 4 lists code for“VideoTypeViewController.m,” Appendix 5 lists code for“VideoTypeViewController.h,” Appendix 6 lists code for“VideoInformationScreen.m,” Appendix 7 lists code for“VideoInformationScreen.h,” Appendix 8 lists code for“CameraInstructionsViewController.m,” Appendix 9 lists code for“CameraInstructionsViewController.h,” Appendix 10 lists code for“Overlay ViewController.m,” Appendix 11 lists code for “OverlayViewController.h,” Appendix 12 lists code for“VideoInstructionsViewController.m” and Appendix 13 lists code for“VideoInstructionsViewController.h.”

An example of a video upload process is shown in FIG. 36. The processcan include a first step of prompting the user to start a videoprescreening tool, and a second step of prompting the user to pick avideo from a library (such as a video in a Camera Roll, where an iPhone,iPad or iTouch is used as the input device) or take a new video. If theuser elects to take a new video, the user is given suggestions orinstructions, prompted to start recording and guided through amulti-step analytical process, which may, in one embodiment, include 9steps. Upon completion of the recording, the user can be returned to thethird step in the process. The process can include a third step ofprompting the user to enter an email address, the child's age and thegender of the child. The process can include a fourth step of uploadingthe video; and a fifth step of displaying a confirmation to the user.

The invention can also include a virtual machine to enable thevideo-based and parent/caregiver based classification of individualssuspected of autism. This machine can include a unix operating system, awebserver, Django framework and a MySQL relational database to storeinformation about the users and videos. This machine enables a user toenter a portal authenticated via Django's built-in user authenticationsystem (usernames and passwords are stored in a hashed table in theMySQL database). It then enables this authenticated user to providedetailed information on medical history, and to answer the questionsassociated with the caregiver-classifier. Next this machine can containall necessary functionality for a user to upload video to anaccess-controlled directory in its original format. The machine containsthe transcoding components including FFmpeg needed to transcode thevideo into .webm and .mp4 formats. The machine contains andautomatically runs code to store details about the video files,including their locations within the file system and metatags.

This machine also contains the tools needed for an analyst to score avideo and compute the video-based classifier. An analyst can securelylogin to the machine and be presented with a list of videos availablefor review sorted in order of priority. Finally the machine containscode and software connections needed to generate a report for both aclinical consumer as well as a caregiver consumer.

The present invention can be used to develop a pre-screening tool forgeneral public use by individuals who are concerned about a particulardisorder but not willing, ready or able to see a professional for aformal assessment and diagnosis or as a pre-screening tool in anyenvironment, be it clinical or non-clinical. The invention can beapplied to any disorder, particularly disorders that are diagnosed usingscreening techniques that may include lengthy and time-consumingquestionnaires and/or observations of behavior to develop apre-screening technique for the disorder. The present invention can beapplied to any disorder that has a behavioral component, that manifestsitself in behavior, that manifests itself in the motion or movement of asubject, that manifests itself in an observable manner or that manifestsitself in a morphological attribute of the subject.

For example, the invention can be applied in the manner described hereinto any mental disorder such as acute stress disorder, adjustmentdisorder, amnesia, anxiety disorder, anorexia nervosa, antisocialpersonality disorder, asperger syndrome, attention deficit/hyperactivitydisorder, autism, autophagia, avoidant personality disorder,bereavement, bestiality, bibliomania, binge eating disorder, bipolardisorder, body dysmorphic disorder, borderline personality disorder,brief psychotic disorder, bulimia nervosa, childhood disintegrativedisorder, circadian rhythm sleep disorder, conduct disorder, conversiondisorder, cyclothymia, delirium, delusional disorder, dementia,dependent personality disorder, depersonalization disorder, depression,disorder of written expression, dissociative fugue, dissociativeidentity disorder, down syndrome, dyslexia, dyspareunia, dyspraxia,dysthymic disorder, erotomania, encopresis, enuresis, exhibitionism,expressive language disorder, factitious disorder, folie a deux, gansersyndrome, gender identity disorder, generalized anxiety disorder,general adaptation syndrome, histrionic personality disorder,hyperactivity disorder, primary hypersomnia, hypochondriasis,hyperkinetic syndrome, hysteria, intermittent explosive disorder,joubert syndrome, kleptomania, mania, munchausen syndrome, mathematicsdisorder, narcissistic personality disorder, narcolepsy, nightmares,obsessive-compulsive disorder, obsessive-compulsive personalitydisorder, oneirophrenia, oppositional defiant disorder, pain disorder,panic attacks, panic disorder, paranoid personality disorder,parasomnia, pathological gambling, perfectionism, pervasivedevelopmental disorder, pica, postpartum depression, post-traumaticembitterment disorder, post-traumatic stress disorder, primary insomnia,psychotic disorder, pyromania, reading disorder, reactive attachmentdisorder, retts disorder, rumination syndrome, schizoaffective disorder,schizoid, schizophrenia, schizophreniform disorder, schizotypalpersonality disorder, seasonal affective disorder, self injury,separation anxiety disorder, sadism and masochism, shared psychoticdisorder, sleep disorder, sleep terror disorder, sleepwalking disorder,social anxiety disorder, somatization disorder, stereotypic movementdisorder, stuttering, suicide, tourette syndrome, transient ticdisorder, trichotillomania and the like.

As shown, for example, in FIG. 37, the present invention can include acomputer implemented method of generating a diagnostic tool 60 of aninstrument for diagnosis of a disorder 10, wherein the instrumentcomprises a full set of diagnostic items. The computer implementedmethod can comprise on a computer system 20 having one or moreprocessors 30 and a memory 40 storing one or more computer programs 50for execution by the one or more processors 30, the one or more computerprograms 50 including instructions for implementing the method,described in detail herein. The present invention can also include anon-transitory computer-readable storage medium storing the one or morecomputer programs 50, which, can, in turn, be installed on the computersystem 20.

In the present application, each client can include a clientapplication. The client can be any number of devices (e.g., computer,internet kiosk, personal digital assistant, cell phone, gaming device,desktop computer, laptop computer, tablet computer, a television withone or more processors embedded therein or attached thereto, or aset-top box) which can be used to connect to a communication network.The communication network can be a wireless, optical, wired or othertype of network that facilitates the passage of information. It caninclude the Internet, one or more local area networks (LANs), one ormore wide area networks (WANs), other types networks, or a combinationof such networks. The client application is an application that isexecuted by the client (e.g., browser, e-mail client, word processor)and that displays or presents information to a user of the client (theclient application can also perform other tasks not relevant to thepresent discussion). Client can also include a location determiner forreporting a geolocation of the client.

A customer client system can include one or more processing units(CPU's), one or more network or other communications interfaces, memory,and one or more communication buses for interconnecting thesecomponents. The customer client system can include a user interface, forinstance a display and a keyboard. The memory can include high speedrandom access memory and can also include non-volatile memory, such asone or more magnetic or optical storage disks. The memory can includemass storage that is remotely located from CPU's. The memory can storethe following elements, or a subset or superset of such elements: anoperating system that includes procedures for handling various basicsystem services and for performing hardware dependent tasks; a networkcommunication module (or instructions) that is used for connecting thecustomer client system to other computers via the one or morecommunications interfaces (wired or wireless), such as the Internet,other wide area networks, local area networks, metropolitan areanetworks, and so on; a client application as described above; a clientassistant as described above; optionally, a cache of downloaded and acache downloaded, as well as other information for viewing using theclient application, and information retrieved by user selection of oneor more items.

Although some of various drawings illustrate a number of logical stagesin a particular order, stages which are not order dependent can bereordered and other stages can be combined or broken out. Alternativeorderings and groupings, whether described above or not, can beappropriate or obvious to those of ordinary skill in the art of computerscience. Moreover, it should be recognized that the stages could beimplemented in hardware, firmware, software or any combination thereof.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of thepresent invention, in addition to those described herein, will beapparent to those of ordinary skill in the art from the foregoingdescription and accompanying drawings. Thus, such modifications areintended to fall within the scope of the invention. Furthermore, manyfunctions described herein can be implemented in hardware or insoftware. Further, software descriptions of the invention can be used toproduce hardware implementing the invention. Software can be embodied onany known non-transitory computer-readable medium having embodiedtherein a computer program for storing data. In the context of thisdocument, a computer-readable storage medium can be any tangible mediumthat can contain, or store a program for use by or in connection with aninstruction execution system, apparatus, or device. A computer-readablestorage medium can be, for example, an electronic, magnetic, optical,electromagnetic, infrared, or semiconductor system, apparatus, ordevice, or any suitable combination of the foregoing. More specificexamples of the computer-readable storage medium include the following:a portable computer diskette, a hard disk, a random access memory (RAM),a read-only memory (ROM), an erasable programmable read-only memory(EPROM or Flash memory), a portable compact disc read-only memory(CD-ROM), an optical storage device, a magnetic storage device, or anysuitable combination of the foregoing. Further, although aspects of thepresent invention have been described herein in the context of aparticular implementation in a particular environment for a particularpurpose, those of ordinary skill in the art will recognize that itsusefulness is not limited thereto and that the present invention can bebeneficially implemented in any number of environments for any number ofpurposes.

The foregoing description, for purpose of explanation, has beendescribed with reference to specific embodiments. However, theillustrative discussions above are not intended to be exhaustive or tobe limiting to the precise forms disclosed. Many modifications andvariations are possible in view of the above teachings. The embodimentswere chosen and described in order to best explain the principles of theaspects and its practical applications, to thereby enable others skilledin the art to best utilize the aspects and various embodiments withvarious modifications as are suited to the particular use contemplated.

1. A computer-implemented method for evaluating and treating a subjectfor a behavioral disorder, a developmental delay, or a neurologicalimpairment, said method comprising: (a) receiving an input; (b)providing the input to a classifier that is trained with data from aplurality of individuals having the behavioral disorder, thedevelopmental delay, or the neurological impairment and that isconfigured to evaluate the subject with respect to the behavioraldisorder, the developmental delay, or the neurological impairment basedon the input; (c) determining an evaluation result with the classifier;and (d) treating the subject for the behavioral disorder, thedevelopmental delay, or the neurological impairment based on theevaluation result.
 2. The method of claim 1, wherein the treatment isbased on a severity of the behavioral disorder, the developmental delay,or the neurological impairment.
 3. The method of claim 1, wherein thetreatment comprises at least one of applied behavioral analysis (ABA) ora speech therapy.
 4. The method of claim 1, wherein the treatment isprovided by the computer.
 5. The method of claim 1, further comprisingdetermining a treatment plan for treating the subject based on theevaluation result.
 6. The method of claim 1, further comprising scoringthe subject based on the evaluation result, wherein said score isindicative of a likelihood of a presence or an absence of the behavioraldisorder, the developmental delay, or the neurological impairment insaid subject.
 7. The method of claim 6, wherein the final scorecomprises a magnitude, and wherein the magnitude of the final score isindicative of one or more of a severity of the behavioral disorder, thedevelopmental delay, or the neurological impairment or a confidence inthe evaluation result.
 8. The method of claim 1, further comprisingtransforming the input into discrete numerical vectors, and wherein thediscrete numerical vectors are provided to the classifier to determinethe evaluation result.
 9. The method of claim 1, wherein the input isobtained using a mobile computing device.
 10. The method of claim 9,wherein the mobile computing device is a smart device.
 11. The method ofclaim 10, wherein the smart device is a smart phone or a tablet.
 12. Themethod of claim 1, wherein the input comprises a video of the subject.13. The method of claim 1, wherein the classifier is generated using amachine learning technique selected from the group consisting of ADTree,BFTree, DecisionStump, FT, J48, J48graft, Jrip, LADTree, LMT, Nnge,OneR, PART, RandomTree, REPTree, Ridor and SimpleCart.
 14. The method ofclaim 1, wherein the classifier is configured to evaluate astatistically accurate set of items as the input to allow efficientevaluation.
 15. The method of claim 1, wherein the evaluation result isbased on the Autism Diagnostic Instrument-Revised or the AutismDiagnostic Observation Schedule.
 16. The method of claim 1, wherein thebehavioral disorder, the developmental delay, or the neurologicalimpairment comprises ADHD, autism, or autism spectrum disorder.
 17. Asystem for evaluating and treating a subject for a behavioral disorder,a developmental delay, or a neurological impairment, said computersystem comprising: a processor; and a classifier that is trained withdata from a plurality of individuals having the behavioral disorder, thedevelopmental delay, or the neurological impairment and is configured toevaluate the subject with respect to the behavioral disorder, thedevelopmental delay, or the neurological impairment; a non-transitorycomputer readable medium that stores instructions that when executed bythe processor causes the processor to: receive an input related to thebehavioral disorder, the developmental delay, or the neurologicalimpairment; provide the input to the classifier; receive an evaluationresult from the classifier related to the behavioral disorder, thedevelopmental delay, or the neurological impairment; and provide atreatment to the subject for the behavioral disorder, the developmentaldelay, or the neurological impairment based on the evaluation result.18. The system of claim 17, wherein the behavioral disorder, thedevelopmental delay, or the neurological impairment comprises ADHD,autism, or autism spectrum disorder.
 19. The system of claim 17, whereinthe treatment comprises at least one of applied behavioral analysis(ABA) or a speech therapy.
 20. The system of claim 17, wherein thetreatment comprises a treatment plan for treating the subject based onthe evaluation result.